Drugs List

Therapeutic Indications

Uses

Depression - severe

Contraindications

Children under 18 years
Within 2 weeks of discontinuing MAOIs
Galactosaemia
Hereditary fructose intolerance

Precautions and Warnings

Elderly
Predisposition to hyponatraemia
Suicidal ideation
Acute narrow angle glaucoma
Angina
Benign prostatic hyperplasia
Bipolar disorder
Breastfeeding
Cardiac conduction defects
Diabetes mellitus
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of seizures
Hypotension
Lactose intolerance
Organic brain syndrome
Phenylketonuria
Pregnancy
Psychosis
Raised intra-ocular pressure
Recent myocardial infarction
Renal impairment - creatinine clearance below 40ml/minute
Schizophrenia
Urinary obstruction

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Patients at risk of suicide should be closely supervised
Some formulations contain aspartame - caution in phenylketonuria
Advise ability to drive/operate machinery may be affected by side effects
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Some brands contain Sunset Yellow (E110) - can trigger allergic reactions
Some formulations contain lactose
Some formulations contain sucrose
Discontinue treatment if patient develops seizures
May cause hyponatraemia
Monitor antidiabetic drug treatment
Monitor for signs of blood dyscrasias eg fever, sore throat, malaise etc
Monitor for signs of bone marrow depression
Monitor patients for adverse reactions including restlessness & agitation
Advise patients/carers to seek medical advice if suicidal intent develops
Potential for withdrawal symptoms
Avoid abrupt withdrawal
To discontinue, reduce dose gradually
Discontinue at first signs of jaundice
Discontinue if patient enters a manic phase
Discontinue immediately if suspicion of a blood dyscrasia
Limit prescribing quantity due to suicide risk
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of self harm is highest shortly after presentation and the risk of suicide may increase again in the early stages of recovery. Furthermore, there is evidence that in children and adolescents, antidepressants may increase the risk of suicidal thoughts and self harm.

Patients with a history of suicide related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults (up to 25 years), are at a greater risk of suicidal thought or suicide attempt, and should receive careful monitoring during treatment.

Patients, (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal thoughts and behaviour, and to seek medical advice immediately if these symptoms present.

If the patient is not doing well after starting treatment the possibility of an adverse reaction should be considered. Patients should be monitored for signs of psychomotor restlessness or agitation, particularly at the beginning of treatment. Increasing the dose in these circumstances may be detrimental, and it may be necessary to review the use of mirtazapine.

Pregnancy and Lactation

Pregnancy

In pregnancy mirtazapine should only be used with caution and with monitoring of the infant.

There is less clinical experience in pregnancy with mirtazapine than some of the other antidepressants, Schaefer states that it is a drug of second choice. The use of mirtazapine is not an indication for termination of pregnancy. Furthermore a pregnant patient who is stable with mirtazapine should not be switched to another drug because this may worsen her health. A detailed foetal ultrasonography may be offered after use in the first trimester. Briggs reports successful healthy pregnancies following exposure to mirtazapine with normal follow up. A study however looking at exposure of mirtazapine in pregnant women against disease matched controls found more preterm births and significantly fewer live births in women compared to nonteratogen-exposed controls and more spontaneous abortions in the group exposed to mirtazapine. There were 104 pregnancy outcomes in each of the three groups with 95% taking mirtazapine throughout the first trimester and 25% throughout gestation. The outcome was there was 20 spontaneous abortions, 6 elective abortions, 1 stillbirth and 77 live births. Two major malformations were reported (unspecified). The study concluded that mirtazapine does not appear to increase the baseline rate of major malformations of 1% to 3%. But the finding that there were more spontaneous abortions in the antidepressant groups is in agreement with previous studies.
The only statistically significant finding from this study was an increase in the rate of pre-term delivery (prior to 37 weeks) with mirtazapine (10%) compared to control (2%).

A prospective cohort study looking at antidepressant exposure during the first trimester of pregnancy found that in 68 pregnant women on mirtazapine two of the infants developed major anomalies: tracheomalacia and vesicoureteral reflux.

Observation of the neonate for withdrawal symptoms or adaptation problems for at least the first 2 days is recommended when mirtazapine is used up to delivery. To prevent neonatal adaption disorders, dose reduction or even treatment interruption in the days immediately preceding delivery can be discussed with the patient if the clinical course allows. However to prevent a relapse at this vulnerable stage, pre-pregnancy dosage should be started immediately after delivery.

It is not known if mirtazapine crosses the placenta to the foetus but because of its low molecular weight (about 265) and prolonged elimination half life, transfer to the embryo and/or foetus should be anticipated.

Data from experience with pregnant animals

No teratogenic effects were observed in the offspring of rats and rabbits given doses of up to 20 and 17 times, respectively, the maximum recommended human dose based on body surface area. However toxicity was observed in rats which included an increase in post-implantation losses. There was also an increase in pup deaths during the first three days of lactation (cause of death unknown) and lower pup birth weights at the maximum dose. This developmental toxicity wasn't seen with a dose that was 15% of the maximum dose (approximately three times the maximum recommended human dose).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

In breastfeeding mirtazapine should only be used with caution and with monitoring of the infant.

There is limited data on the use of mirtazapine in breastfeeding mothers, mirtazapine is present in breast milk however the infants in the studies were reported to have developed normally. If mirtazapine is used the infant should be monitored for sedation. Briggs states that although no adverse effects have been reported, the long term effects on neurobehaviour and development from exposure to this class of agents during this period of rapid CNS development has not been studied.

Data from Lactmed supports the fact that mirtazapine is excreted in low levels in the breast milk of mothers when given in licensed doses. They state that mirtazapine should not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Mirtazapine is not a reason to discontinue breastfeeding however exclusively breastfed infants should be monitored for changes in behaviour and adequate growth. Generally the reported cases on Lactmed describe no sedation or abnormal weight gain attributable to mirtazapine though one report may indicate sedation no causality could be established. The Maudsley prescribing guidelines concur and reported that all eight infants exposed through breast milk in a study all showed normal developmental milestones, though they note serum levels may vary due to differences in mirtazapine elimination between individual infants.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Aggression
Agitation
Agranulocytosis
Akathisia
Anxiety
Aplastic anaemia
Arthralgia
Back pain
Bone marrow depression
Bullous dermatoses
Confusion
Convulsions
Diarrhoea
Dizziness
Dream abnormalities
Drowsiness
Dry mouth
Eosinophilia
Erythema multiforme
Exanthema
Fatigue
Granulocytopenia
Hallucinations
Headache
Hyperkinesia
Hyperprolactinaemia
Hypersalivation
Hypertriglyceridaemia
Hyponatraemia
Hypotension
Inappropriate secretion of antidiuretic hormone
Increase in serum transaminases
Increased appetite
Increases in hepatic enzymes
Insomnia
Jaundice
Lethargy
Mania
Myalgia
Myoclonus
Narrow angle glaucoma
Nausea
Nightmares
Oedema
Oral hypoaesthesia
Oral oedema
Oral paraesthesia
Paraesthesia
Peripheral oedema
Postural hypotension
Psychomotor restlessness
Rash
Restless legs
Sedation
Serotonin syndrome
Sleep walking
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Syncope
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urticaria
Vomiting
Weight gain

Presentation

Oral formulations containing mirtazapine.

Drugs List

Therapeutic Indications

Uses

Depression - severe

Dosage

Duration of treatment:
Treatment should preferably be continued until the patient has been symptom free for at least 6 months. After this treatment can be gradually discontinued.
In general, mirtazapine begins to exert its effect after 1 to 2 weeks of treatment. A positive response to an adequate dose should occur within 2 to 4 weeks.
If response is insufficient, the dose can be increased up to the maximum dose. If there is no response within a further 2 to 4 weeks treatment should be stopped.

Adults

Elderly

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Contraindications

Children under 18 years
Within 2 weeks of discontinuing MAOIs
Galactosaemia
Hereditary fructose intolerance

Precautions and Warnings

Elderly
Predisposition to hyponatraemia
Suicidal ideation
Acute narrow angle glaucoma
Angina
Benign prostatic hyperplasia
Bipolar disorder
Breastfeeding
Cardiac conduction defects
Diabetes mellitus
Epileptic disorder
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of seizures
Hypotension
Lactose intolerance
Organic brain syndrome
Phenylketonuria
Pregnancy
Psychosis
Raised intra-ocular pressure
Recent myocardial infarction
Renal impairment - creatinine clearance below 40ml/minute
Schizophrenia
Urinary obstruction

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Patients at risk of suicide should be closely supervised
Some formulations contain aspartame - caution in phenylketonuria
Advise ability to drive/operate machinery may be affected by side effects
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Some brands contain Sunset Yellow (E110) - can trigger allergic reactions
Some formulations contain lactose
Some formulations contain sucrose
Discontinue treatment if patient develops seizures
May cause hyponatraemia
Monitor antidiabetic drug treatment
Monitor for signs of blood dyscrasias eg fever, sore throat, malaise etc
Monitor for signs of bone marrow depression
Monitor patients for adverse reactions including restlessness & agitation
Advise patients/carers to seek medical advice if suicidal intent develops
Potential for withdrawal symptoms
Avoid abrupt withdrawal
To discontinue, reduce dose gradually
Discontinue at first signs of jaundice
Discontinue if patient enters a manic phase
Discontinue immediately if suspicion of a blood dyscrasia
Limit prescribing quantity due to suicide risk
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of self harm is highest shortly after presentation and the risk of suicide may increase again in the early stages of recovery. Furthermore, there is evidence that in children and adolescents, antidepressants may increase the risk of suicidal thoughts and self harm.

Patients with a history of suicide related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults (up to 25 years), are at a greater risk of suicidal thought or suicide attempt, and should receive careful monitoring during treatment.

Patients, (and caregivers of patients) should be alerted about the need to monitor for the emergence of suicidal thoughts and behaviour, and to seek medical advice immediately if these symptoms present.

If the patient is not doing well after starting treatment the possibility of an adverse reaction should be considered. Patients should be monitored for signs of psychomotor restlessness or agitation, particularly at the beginning of treatment. Increasing the dose in these circumstances may be detrimental, and it may be necessary to review the use of mirtazapine.

Pregnancy and Lactation

Pregnancy

In pregnancy mirtazapine should only be used with caution and with monitoring of the infant.

There is less clinical experience in pregnancy with mirtazapine than some of the other antidepressants, Schaefer states that it is a drug of second choice. The use of mirtazapine is not an indication for termination of pregnancy. Furthermore a pregnant patient who is stable with mirtazapine should not be switched to another drug because this may worsen her health. A detailed foetal ultrasonography may be offered after use in the first trimester. Briggs reports successful healthy pregnancies following exposure to mirtazapine with normal follow up. A study however looking at exposure of mirtazapine in pregnant women against disease matched controls found more preterm births and significantly fewer live births in women compared to nonteratogen-exposed controls and more spontaneous abortions in the group exposed to mirtazapine. There were 104 pregnancy outcomes in each of the three groups with 95% taking mirtazapine throughout the first trimester and 25% throughout gestation. The outcome was there was 20 spontaneous abortions, 6 elective abortions, 1 stillbirth and 77 live births. Two major malformations were reported (unspecified). The study concluded that mirtazapine does not appear to increase the baseline rate of major malformations of 1% to 3%. But the finding that there were more spontaneous abortions in the antidepressant groups is in agreement with previous studies.
The only statistically significant finding from this study was an increase in the rate of pre-term delivery (prior to 37 weeks) with mirtazapine (10%) compared to control (2%).

A prospective cohort study looking at antidepressant exposure during the first trimester of pregnancy found that in 68 pregnant women on mirtazapine two of the infants developed major anomalies: tracheomalacia and vesicoureteral reflux.

Observation of the neonate for withdrawal symptoms or adaptation problems for at least the first 2 days is recommended when mirtazapine is used up to delivery. To prevent neonatal adaption disorders, dose reduction or even treatment interruption in the days immediately preceding delivery can be discussed with the patient if the clinical course allows. However to prevent a relapse at this vulnerable stage, pre-pregnancy dosage should be started immediately after delivery.

It is not known if mirtazapine crosses the placenta to the foetus but because of its low molecular weight (about 265) and prolonged elimination half life, transfer to the embryo and/or foetus should be anticipated.

Data from experience with pregnant animals

No teratogenic effects were observed in the offspring of rats and rabbits given doses of up to 20 and 17 times, respectively, the maximum recommended human dose based on body surface area. However toxicity was observed in rats which included an increase in post-implantation losses. There was also an increase in pup deaths during the first three days of lactation (cause of death unknown) and lower pup birth weights at the maximum dose. This developmental toxicity wasn't seen with a dose that was 15% of the maximum dose (approximately three times the maximum recommended human dose).

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

In breastfeeding mirtazapine should only be used with caution and with monitoring of the infant.

There is limited data on the use of mirtazapine in breastfeeding mothers, mirtazapine is present in breast milk however the infants in the studies were reported to have developed normally. If mirtazapine is used the infant should be monitored for sedation. Briggs states that although no adverse effects have been reported, the long term effects on neurobehaviour and development from exposure to this class of agents during this period of rapid CNS development has not been studied.

Data from Lactmed supports the fact that mirtazapine is excreted in low levels in the breast milk of mothers when given in licensed doses. They state that mirtazapine should not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Mirtazapine is not a reason to discontinue breastfeeding however exclusively breastfed infants should be monitored for changes in behaviour and adequate growth. Generally the reported cases on Lactmed describe no sedation or abnormal weight gain attributable to mirtazapine though one report may indicate sedation no causality could be established. The Maudsley prescribing guidelines concur and reported that all eight infants exposed through breast milk in a study all showed normal developmental milestones, though they note serum levels may vary due to differences in mirtazapine elimination between individual infants.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Aggression
Agitation
Agranulocytosis
Akathisia
Anxiety
Aplastic anaemia
Arthralgia
Back pain
Bone marrow depression
Bullous dermatoses
Confusion
Convulsions
Diarrhoea
Dizziness
Dream abnormalities
Drowsiness
Dry mouth
Eosinophilia
Erythema multiforme
Exanthema
Fatigue
Granulocytopenia
Hallucinations
Headache
Hyperkinesia
Hyperprolactinaemia
Hypersalivation
Hypertriglyceridaemia
Hyponatraemia
Hypotension
Inappropriate secretion of antidiuretic hormone
Increase in serum transaminases
Increased appetite
Increases in hepatic enzymes
Insomnia
Jaundice
Lethargy
Mania
Myalgia
Myoclonus
Narrow angle glaucoma
Nausea
Nightmares
Oedema
Oral hypoaesthesia
Oral oedema
Oral paraesthesia
Paraesthesia
Peripheral oedema
Postural hypotension
Psychomotor restlessness
Rash
Restless legs
Sedation
Serotonin syndrome
Sleep walking
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Syncope
Thrombocytopenia
Toxic epidermal necrolysis
Tremor
Urticaria
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: March 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Joint Formulary Committee. British National Formulary. 66th ed. London: BMJ Group and Pharmaceutical Press; 2013. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press https://www.medicinescomplete.com [Accessed on March 11, 2014].

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Psychotropic Drug Directory (2009) Bazire, S. HealthComm UK Ltd, Aberdeen.

The Maudsley Prescribing Guidelines in Psychiatry, 11th edition (2012). Taylor, D., Paton, C and Kapur, S. Wiley-Blackwell, West Sussex.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

Summary of Product Characteristics: Mirtazapine 15mg/ml oral solution. Rosemont Pharmaceuticals Limited. Revised October 2010.
Summary of Product Characteristics: Mirtazapine orodispersible tablets 45mg. Aurobindo Pharma -Milpharm Ltd. Revised October 2012.
Summary of Product Characteristics: Mirtazapine orodispersible tablets 15mg. Actavis UK Ltd. Revised December 2013.
Summary of Product Characteristics: Mirtazapine orodispersible tablets 45mg. Sandoz Limited. Revised September 2013.
Summary of Product Characteristics: Mirtazapine tablets 45mg. Actavis UK Ltd. Revised February 2014.
Summary of Product Characteristics: Mirtazapine tablets 45mg. Aurobindo Pharma - Milpharm Ltd. Revised August 2013.
Summary of Product Characteristics: Mirtazapine tablets 30mg. Sandoz Limited. Revised March 2013.
Summary of Product Characteristics: Zispin SolTab 15mg, 30mg and 45mg Orodispersible Tablets. Merck Sharp & Dohme Limited. Revised August 2019.

MHRA Press Release: Implementation of warnings on suicidal thoughts and behaviour in antidepressants February 4, 2008.
https://www.mhra.gov.uk/NewsCentre/Pressreleases/CON2033960
Last accessed: March 12, 2014

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Mirtazapine Last revised: January 16, 2014
Last accessed: March 12, 2014