Mirtazapine (Remeron) is a tetracyclic antidepressant drug that is used in the treatment of unipolar major depression, anxiety with panic attacks, and chronic headache.

Mirtazapine (Remeron) Uses:

• Major depressive disorder (unipolar):

  • Treatment of unipolar major depressive disorder (MDD)

• Off Label Use of Mirtazapine in Adults:

  • Prophylaxis of chronic tension-type Headache
  • Panic disorder

Mirtazapine Dose in Adults:

Mirtazapine (Remeron) Dose as alternative agent  in the prophylaxis of chronic tension-type headache:

• Oral: Initial: 15 mg once a day at bedtime;
• The dose may be increased after 1 week to 30 mg/day based on response and tolerability.

Mirtazapine (Remeron) Dose in the treatment of unipolar major depressive disorder:

• Oral: Initial: 15 mg once a day at bedtime;
• Depending on response and tolerance, the dose may be increased in 15 mg increments no less frequently than once or twice every two weeks.
• Maximum dose: 45 mg/day (product labelling); clinical trials have utilised dosages as high as 60 mg/day.

Mirtazapine (Remeron) Dose as an alternative agent in the treatment of the Panic disorder (off-label):

Note: Comparable to monotherapy or supplementary therapy for patients who do not respond to SSRIs

• Oral: Initial: 15 mg once a day at bedtime;
• Depending on response and tolerance, the dose may be increased by 15 mg increments at intervals of no less than 1 week, with a typical  maximum of 45 mg administered once daily (product labeling).
• However, despite doses up to 60 mg/day having been tested, the typical dose in clinical trials was only about 30 mg/day.

• Discontinuation of therapy:

  • When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (e.g. over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms.
  • The reasons for a slower titration (eg, over 4 weeks) enlist the use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), earlier history of antidepressant withdrawal symptoms, or high doses of antidepressants.
  • If intolerable withdrawal symptoms appear, resume the previously prescribed dose and/or reduce it more gradually (Shelton 2001).
  • Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months.
  • However, evidence supporting ideal taper rates is limited.

• Switching antidepressants:

  • There is little research to support the best antidepressant switching techniques,
  • They include straight switch and cross-titration (gradually stopping the previous antidepressant while concurrently gradually  increasing the new antidepressant) (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an  equivalent dose or lower dose and increasing it gradually).
  • Cross-titration is recommended for most switches but is not recommended when transitioning to or from an MAOI (e.g., over 1 to  4 weeks depending on susceptibility to withdrawal symptoms and side effects).
  • When switching from one antidepressant to another in the same or similar class (for example, when switching between two SSRIs), a direct switch may be an appropriate strategy if the antidepressant to be discontinued has been used for less than one week or if  the discontinuation is due to side effects.
  • Consider the risk of withdrawal symptoms, the possibility of drug interactions, additional antidepressant features (such as half-life,  side effects, and pharmacodynamics), as well as the desired level of symptom control, while deciding on the switch strategy.

• Switching to or from an MAOI:

  • The time period between stopping an MAOI and starting mirtazapine is 14 days.
  • There must be a 14-day gap between stopping mirtazapine and starting an MAOI.

Use in Children:

Not indicated.

Mirtazapine (Remeron) Pregnancy Risk Category: C

• Mirtazapine crosses the placenta.
• Mirtazapine exposure during pregnancy has not resulted in a significant increase in major teratogenic effect; however, we have limited information.
• Pregnancy treatment with antidepressants should be individualized.
• For some women, psychotherapy and other non-medication therapies might be an option.
• However, pregnant women suffering from moderate to severe major depression should consider antidepressant medication.
• Other agents than mirtazapine may be preferred in cases where MDD treatment is initiated during pregnancy.
• The ACOG and APA have developed treatment algorithms for women suffering from depression before and during pregnancy.

Use Mirtazapine while breastfeeding

• Breast milk contains Mirtazapine as well as its active metabolite.
• The highest reported relative infant dose (RID), of mirtazapine is 4.4%.
• Researchers calculated the RID after maternal administration of mirtazapine 22.5mg/day to a woman 6 weeks postpartum. However, metabolite concentrations weren't evaluated.
• After the maternal dose, breast milk was tested for 4 hours.
• Breast milk can also contain desmethylmirtazpine.
• If the RID of medication falls below 10%, breastfeeding is generally acceptable.
• Some sources mention that breastfeeding should be considered only if the RID for psychotropic drugs is less than 5%.
• Mirtazapine is detectable in breastfed infant serum. However, adverse reactions have not been reported. One case did report possible sedation or weight gain.
• Mothers who use psychotropic medication should monitor their infants at least once per day for any changes in sleep, feeding, behavior, or neurodevelopment.
• When a breastfeeding female is first starting an antidepressant, she may prefer to use an agent other than mirtazapine.
• Manufacturer suggests caution when breastfeeding females are concerned.

Mirtazapine (Remeron) Dose in Kidney Disease:

There are no dosage adjustments provided in the manufacturer’s labeling; though, clearance is decreased with moderate and severe renal impairment. Use carefully.

Mirtazapine (Remeron) Dose in Liver disease:

However, the manufacturer's labelling does not mention dosage modifications, and even then, hepatic impairment may result in a reduction in clearance. Use  with caution.

Common Side Effects of Mirtazapine (Remeron):

• Central nervous system:

  • Drowsiness

• Endocrine & metabolic:

  • Increased serum cholesterol
  • Weight gain

• Gastrointestinal:

  • Increased appetite
  • Constipation
  • Xerostomia

Less Common Side Effects of Mirtazapine (Remeron):

• Cardiovascular:

  • Hypertension
  • Edema
  • Vasodilation
  • Peripheral Edema

• Central Nervous System:

  • Twitching
  • Abnormal Dreams
  • Malaise
  • Confusion
  • Depression
  • Amnesia
  • Apathy
  • Hypoesthesia
  • Agitation
  • Myasthenia
  • Abnormality In Thinking
  • Paresthesia
  • Anxiety
  • Vertigo
  • Dizziness

• Dermatologic:

  • Skin Rash
  • Pruritus

• Endocrine & Metabolic:

  • Increased Thirst
  • Increased Serum Triglycerides

• Gastrointestinal:

  • Anorexia
  • Acute Abdominal Condition
  • Vomiting
  • Abdominal Pain

• Genitourinary:

  • Urinary Tract Infection
  • Urinary Frequency

• Hepatic:

  • Increased Serum Alanine Aminotransferase

• Neuromuscular & Skeletal:

  • Hyperkinetic Muscle Activity
  • Back Pain
  • Tremor
  • Myalgia
  • Arthralgia
  • Hypokinesia
  • Asthenia

• Respiratory:

  • Increased Cough
  • Dyspnea
  • Sinusitis
  • Flu-Like Symptoms

Rare Side effect of Mirtazapine (Remeron):

• Cardiovascular:

  • Orthostatic hypotension

Contraindications to Mirtazapine (Remeron):

• Hypersensitivity to mirtazapine and any component of the formulation
• MAO inhibitors are used to treat psychiatric disorders. They can be used concurrently or within 14-days of stopping mirtazapine.
• Intravenous or linezolid methyleneblue patients may initiate mirtazapine.

Warnings and precautions

• Akathisia/psychomotor Restlessness

  • The majority of these symptoms will manifest within the first few weeks.
  • However, it may prove to be harmful for these patients to increase their dose.

• Anticholinergic effects

  • It can cause anticholinergic effects such as constipation, xerostomia and blurred vision.
  • Patients with reduced gastrointestinal motility, paralytic and ileus, urinary retentions, BPH, xerostomia, and visual impairments should be cautious.
  • This agent produces a low degree of anticholinergic blocking compared to other antidepressants.

• Arrhythmias

  • QT prolongation, Torsade de Pointes, and Ventricular Fibrillation have all been reported (occasionally).
  • The majority of incidents involve misusing mirtazapine. However, a series of 84 patients receiving single-agent mirtazapine  overdoses failed to find any instances of QT prolongation.
  • Patients with cardiovascular disease and those who have had QT prolongation in the past, as well as patients receiving QT-prolonging drugs, should be cautious.

• Blood dyscrasias

  • If you notice signs or symptoms of neutropenia or agranulocytosis, it should be stopped immediately.

• Depression in the CNS:

  • CNS depression can result, which could impair mental or physical abilities.
  • However, patients should be cautious about tasks that require mental alertness (e.g. Driving or operating machinery.
  • Comparing to other antidepressants, the degree of sedation experienced is moderate to high.

• Dizziness

  • It is possible to feel dizzy, but it isn't clear if tolerance can develop.

• Fractures

  • Antidepressant treatment has been used to treat bone fractures.
  • If an antidepressant-treated person presents with unresolved bone pain or tenderness, swelling, or bruising.

• Hyperlipidemia

  • Triglyceride and serum cholesterol levels may rise as a result.

• Hyponatremia

  • Hyponatremia may occur.
  • Patients at high risk, such as the elderly and those using drugs that can cause hyponatremia, shouldn't receive treatment.

• Ocular effects

  • It may mildly dilate the pupils, which in some situations can result in narrow-angle glaucoma.
  • Patients who have narrow-angle glaucoma risk factors who have not undergone an irisectomy should be assessed.

• Orthostatic hypotension

  • In patients at high risk or those who cannot tolerate brief hypotensive episodes, orthostatic hypotension may develop (risk is  minimal compared to other antidepressants).

• Serotonin syndrome

  • Serotonin Syndrome is a potentially fatal side effect of certain serotonergic medications, such as SSRIs (SS).
  • SSRIs and SNRIs are frequently used with other serotonergic medications (such as Buspirone, fentanyl, or tramadol  can all be used with triptans, TCAs, and fentanyl. Mental diseases are treated with MAO inhibitors.
  • Other MAO inhibitors (for instance, intravenous Methylene Blue and linezolid).
  • Patients need to be closely watched for symptoms of SS, such as altered mental status (such as agitation, hallucinations, and  delirium); coma; autonomic instability (such as tachycardia; labile blood pressure, diaphoresis; neuromuscular changes such as  tremor, rigidity, and myoclonus; GI symptoms (such as nausea, vomiting, and diarrhoea); and seizures.
  • The course of treatment will be halted right once if any symptoms or signs appear (along with any serotonergic agents)

• Sexual dysfunction

  • Mirtazapine has a lower incidence of sexual dysfunction than SSRIs.

• Weight loss

  • It can increase appetite and stimulate weight growth.

• Hepatic impairment

  • Patients with hepatic impairment should be cautious.
  • Transaminase elevations that are clinically significant have been observed.

• Hypomania/mania:

  • This could lead to hypomania or mania in bipolar disorder patients.
  • Patients with bipolar disorder should avoid monotherapy.
  • Patients with depressive symptoms need to be tested for bipolar disorder.
  • This should include details about family history, suicide attempts, bipolar disorder, depression, and other mental health issues.
  • Mirtazapine has not been approved by the FDA for treatment of bipolar disorder.

• Renal impairment

  • In cases of moderate and severe renal impairment, clearance is decreased. Patients with renal impairment, however, need to  exercise caution.

• Seizure disorder

  • Patients at high risk of seizures should be used with caution.

Mirtazapine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Patients should be monitored for any agranulocytosis or severe neutropenia symptoms, such as sore throat, stomatitis, or other infection-related symptoms or a low WBC.
• Renal function
• Hepatic function
• Mental Health
• Lipid profile
• Serotonin syndrome
• Weight gain

How to administer Mirtazapine (Remeron)?

Without regard to meals, it is given orally.

Orally disintegrating tablet:

• Place the tablet on your tongue after opening the blister pack.
• There is no need to split the pill because it is designed to dissolve on the tongue without water.

Mechanism of action of Mirtazapine (Remeron):

• Tetracyclic antidepressant mirtazapine functions by inhibiting central presynaptic beta-adrenergic receptors.
• Serotonin and norepinephrine are released more frequently as a result of this.
• Along with being a potent peripheral alpha-adrenergic antagonist and muscarinic antagonist, it also competes with 5-HT-2 and 5-HT-3  serotonin and H histamine receptors.
• It does not prevent norepinephrine and serotonin from being reuptaken.

Absorption:

• Rapid and complete

Protein binding:

• About 85%

Metabolism:

• It is extensively metabolized in the liver via CYP1A2, 2D6, 3A4 and via demethylation and hydroxylation

Bioavailability:

• About 50%

Half-life elimination:

• 20 to 40 hours;
• increased with renal or hepatic impairment

Time to peak serum concentration:

• About 2 hours

Excretion:

• Urine (75%) and feces (15%) as metabolites

International Brand Names of Mirtazapine:

• Remeron
• Remeron SolTab
• APO-Mirtazapine
• Auro-Mirtazapine
• Auro-Mirtazapine OD
• DOM-Mirtazapine
• JAMP-Mirtazapine
• MYLAN-Mirtazapine
• PMS-Mirtazapine
• PRO-Mirtazapine
• Remeron
• Remeron RD
• RIVA-Mirtazapine [DSC]
• SANDOZ Mirtazapine
• TEVA-Mirtazapine
• TEVA-Mirtazapine OD
• Afloyan
• Aurozapine
• Avanza
• Avanza Soltab
• Axit
• Calixta
• Ciblex
• Comment
• Espirtal
• Menelat
• Mi Er Ning
• Mirap
• Mirastad
• Mirazep
• Mirez
• Miro
• Mirta TD
• Mirtapax
• Mirtapil
• Mirtaz
• Mirtazon
• Mirtel
• Mirtimash
• Mitrapil
• Norset
• Noxibel
• Odonazin
• Rapine
• Reflex
• Remergil
• Remergon
• Remeron
• Remeron SolTab
• Remeron Soltab
• Remirta
• Remirta OD
• Remixil ODT
• Resant
• Sinmaron
• Tazeurin
• Trazapin
• U-Mirtaron
• Vastat Flas
• Zamir
• Zapex
• Zapimet
• Zismirt
• Zispin
• Zulin

Mirtazapine Brand Names in Pakistan: