Mirtazapine

Registered South African indications:

• Major depressive illness

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Children and adolescents below 18 years
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use

Cautions

South African manufacturer recommendations

• Moderate to severe renal impairment
• Hepatic impairment 
• Elderly 
• History of suicide-related events
• Significant suicidal ideation
• History of seizures 
• Organic brain symptoms 
• Cardiac diseases
  - Conduction disturbances
  - Angina pectoris
  - Recent myocardial infarction
• Low blood pressure
• Diabetes mellitus
• Psychotic disorders
  - Schizophrenia
• History of mania or hypomania
• Abrupt withdrawal
• Micturition disturbances
  - Prostate hypertrophy
• Eye disorders
  - Closed-angle glaucoma
  - Raised intraocular pressure 
• Known cardiovascular disease
• Family history of QT prolongation 
• Known risk factors for QT prolongation
• Risk for hyponatraemia
• Coadministration with agents known to cause hyponatraemia
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption 
• May impair ability to drive and operate machinery

International manufacturer recommendations

• Pregnancy 
• Breastfeeding 
• Moderate to severe renal impairment 
• Hepatic impairment 
• Elderly 
• Children and adolescents below 18 years
• History of suicide-related events 
• Significant suicidal ideation  
• Organic brain syndrome 
• History of seizures 
• Cardiac disease
  - Conduction disturbances
  - Angina pectoris
  - Recent myocardial infarction
• Low blood pressure 
• Diabetes mellitus
• Psychotic disorders
  - Schizophrenia
• History of mania or hypomania 
• Abrupt withdrawal 
• Micturition disturbances
  - Prostate hypertrophy
• Acute narrow-angle glaucoma  
• Increased intraocular pressure 
• Known cardiovascular disease
• Family history of QT prolongation 
• Known risk factors for QT prolongation 
• Risk for hyponatraemia 
• Coadministration with agents known to cause hyponatraemia
• Galactose intolerance 
• Total lactase deficiency 
• Glucose-galactose malabsorption 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

Major depressive illness 

South African manufacturer recommendations

• Oral (fct, tab): Initial: 15mg, dly at bedtime; Titrate at intervals of 1-2 weeks; Maintenance: 15-45mg, dly; Acute depressive episodes: ≥6 months; Max: 45mg/24hrs

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Daily doses may be given as a single dose or in two equally divided doses

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Discontinue treatment gradually to reduce risk of withdrawal symptoms 

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International manufacturer recommendations

Episodes of major depression

Oral (fct, tab): Initial: 15-30mg, dly at bedtime; Maintenance: 15-45mg, dly; Treatment duration: ≥6 months; Max: 45mg/24hrs

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May be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night)

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Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks

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With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped

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Discontinue treatment gradually to reduce risk of withdrawal symptoms

Not established for use in children below 18 years

Pregnancy 

South African manufacturer recommendations

• Contraindicated

International manufacturer recommendations

• Caution 
• Limited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed
• Epidemiological data have suggested that the use of selective serotonin reuptake inhibitors (SSRIs) in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations)
• Caution should be exercised when prescribing to pregnant women. If mirtazapine is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects

Breastfeeding 

South African manufacturer recommendations

• Contraindicated 

International manufacturer recommendations

• Caution 
• Animal studies and limited human data have shown excretion of mirtazapine in breast milk only in very small amounts. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with mirtazapine should be made taking into account the benefit of breastfeeding to the child and the benefit of mirtazapine therapy to the woman 

Fertility 

South African manufacturer recommendations

• No information available 

International manufacturer recommendations

• Non-clinical reproductive toxicity studies in animals did not show any effect on fertility

Renal Impairment

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; no dose adjustment recommended 

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended 
• Severe: Caution; no information available 

Elderly

• Caution; no dose adjustment recommended 
  Undesirable effects have not been reported more often in elderly patients
  Increase in dosing should be done under close supervision to elicit a satisfactory and safe response

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings 

Central Nervous System Disorders

• Abnormal dreams
• Confusion
• Anxiety
• Insomnia
• Nightmares
• Mania
• Agitation
• Hallucinations
• Psychomotor restlessness
  - Akathisia
  - Hyperkinesia
• Aggression
• Suicidal ideation
• Suicidal behaviour
• Somnambulism
• Somnolence
• Sedation
• Headache
• Lethargy
• Dizziness
• Tremor
• Amnesia 
• Paraesthesia
• Restless legs 
• Syncope
• Myoclonus
• Seizures
• Serotonin syndrome
• Dysarthria
• Fatigue

Cardiovascular Disorders

• Orthostatic hypotension
• Hypotension

Gastrointestinal Disorders

• Dry mouth
• Nausea and vomiting
• Diarrhoea
• Constipation
• Oral hypoaesthesia
• Mouth oedema
• Increased salivation
• Oral paraesthesia

Hepatobiliary Disorders

• Pancreatitis
• Increased serum transaminases

Genitourinary Disorders

• Urinary retention
• Priapism
• Increased creatinine kinase

Endocrine and Metabolic Disorders

• Inappropriate antidiuretic hormone secretion
• Increased appetite
• Increased weight
• Hyponatraemia
• Hyperprolactinemia
  - Galactorrhoea
  - Gynaecomastia

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Back pain
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Exanthema
• Stevens-Johnson syndrome
• Bullous dermatitis 
• Erythema multiforme
• Toxic epidermal necrolysis
• Drug reaction with eosinophilia and systemic symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Bone marrow depression
  - Granulocytopenia
  - Granulocytosis
  - Aplastic anaemia
  - Thrombocytopenia
• Eosinophilia
• Peripheral oedema
• Generalised oedema
• Localised oedema

• Monoamine oxidase inhibitors
• Serotonergic agents
• L-tryptophan
• Triptans
• Tramadol
• Linezolid
• Selective serotonin reuptake inhibitors (SSRIs)
• Venlafaxine
• Lithium
• Benzodiazepines
• Sedatives
• Antipsychotics
• Antihistamine H₁ antagonists
• Opioids
• Warfarin
• QT-prolonging agents
• Antibiotics
• CYP3A4 inducers
• Carbamazepine
• Rifampicin
• CYP3A4 inhibitors
• Ketoconazole
• Cimetidine
• HIV protease inhibitors
• Azole antifungals
• Erythromycin
• Nefazodone

Other interactions

• Methylene blue
• St John’s wort preparations 
• Alcohol 

• Renal function
• Hepatic function
• Lipid profile
• Weight

Additional observations

• Signs of agranulocytosis or severe neutropenia
  - Sore throat
  - Stomatitis
  - Other signs of infection
  - Low white blood cell count
• Mental alertness
• Depression, clinical worsening, suicidality, or unusual changes in behaviour (e.g. anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, social functioning) (particularly during the initial 1-2 months of therapy or during periods of dosage adjustments)
• Signs/symptoms of serotonin syndrome
  - Mental status changes (e.g. agitation, hallucinations, delirium, coma)
  - Autonomic instability (e.g. tachycardia, labile blood pressure, diaphoresis)
  - Neuromuscular changes (e.g tremor, rigidity, myoclonus)
  - Gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea)
  - Seizures

Mirtazapine is a centrally active presynaptic alpha-₂ antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via serotonin-₁ receptors, because serotonin-₂ and serotonin-₃ receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking alpha-₂ and serotonin-₂ receptors and the R(-) enantiomer by blocking serotonin-₃ receptors.

 

 

Film-coated tablet 15mg

• Adco-Mirteron (Adcock Ingram) 
• Mylan Mirtazapine (Xixia Pharma)
• Mytra (Novagen)
• Remeron (MSD) originator

Tablet 15mg

• Aspen Mirtazapine (Pharmacare)
• Beron (Be-Tabs)
• Miradep (Zydus Healthcare)
• Sandoz Mirtazapine (Sandoz)

Film-coated tablet 30mg

• Adco-Mirteron (Adcock Ingram)
• Mylan Mirtazapine (Xixia Pharma)
• Mytra (Novagen)
• Remeron (MSD) originator

Tablet 30mg

• Aspen Mirtazapine (Pharmacare)
• Beron (Be-Tabs)
• Miradep (Zydus Healthcare)
• Sandoz Mirtazapine (Sandoz)