Drugs List

Therapeutic Indications

Uses

Symptoms of depressive illness especially if sedation required

Contraindications

Children under 18 years
Within 2 weeks of discontinuing MAOIs
Within 2 weeks of discontinuing selegiline
Atrioventricular block
Breastfeeding
Cardiac arrhythmias
Long QT syndrome
Mania
Porphyria
Recent myocardial infarction
Severe hepatic disorder
Torsade de pointes

Precautions and Warnings

Anaesthesia
Elderly
Family history of long QT syndrome
Predisposition to epileptic disorder
Suicidal ideation
Bipolar disorder
Cardiovascular disorder
Diabetes mellitus
Electrolyte imbalance
Epileptic disorder
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of mania
History of torsade de pointes
Hyperthyroidism
Lactose intolerance
Narrow angle glaucoma
Phaeochromocytoma
Pregnancy
Prostate disorder
Psychiatric disorder
Psychosis
Renal impairment
Urinary retention

Anaesthetist should be made aware patient is taking this medication
Correct electrolyte disorders before treatment
Patients at risk of suicide should be closely supervised
Patients with diabetes may experience fluctuations in blood glucose
Advise ability to drive/operate machinery may be affected by side effects
Some formulations contain lactose
Consider monitoring ECG in patients at risk of QT prolongation
Dental check-ups advisable during long-term treatment
Monitor elderly for hyponatraemia if drowsy, confused, fitting
Monitor hepatic function on long term therapy
Monitor serum electrolytes
Advise patients/carers to seek medical advice if suicidal intent develops
Cardiac arrhythmias and severe hypotension with high dosage
Consider hyponatraemia in all patients with drowsiness/confusion/seizures
Increased risk of fractures in patients over 50 years
Life threatening arrhythmias may occur during anaesthesia and surgery
Do not withdraw this drug suddenly
Dosage reduction should be done gradually over about 4 weeks
Reduce dose in elderly
Advise patient not to take St John's wort concurrently
Patient should avoid alcohol as effect may be potentiated

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.

Pregnancy and Lactation

Pregnancy

Use trimipramine with caution in pregnancy.

Tricyclic antidepressants (TCAs), along with SSRIs, are the drug group of choice for treating depression in pregnancy. Extensive epidemiological studies have not shown evidence of a causal relationship between therapeutic doses of TCAs and an increased incidence of congenital malformations or other adverse pregnancy outcomes. However, trimipramine is not the preferred drug within the TCAs; nortriptyline, amitriptyline and imipramine have the lowest known risks during pregnancy as they are least sedative and have fewest maternal adverse effects.

Animal studies with trimipramine have found embryotoxicity and/or an increased incidence of major anomalies at 20x the human dose. This suggests low risk, but human data is too limited to assess the risk to the foetus. It is not known if trimipramine crosses the placenta, but it is likely, given its molecular weight, lipid solubility and long elimination half life. Occasional congenital malformations have been reported, but no causal relationship has been established. The use of trimipramine, despite limited data available compared to the other preferred TCAs, is not an indication for termination. Furthermore, if a pregnant patient is stable on a second-choice TCA such as trimipramine, they should not be changed to another, as this could worsen their health. However, a foetal ultrasonography should be considered.

Maternal serum levels of TCAs should be monitored, with a view to possible dose adjustment, as pharmacokinetics may be altered especially in the second and third trimesters. The usual therapeutic dose may not be sufficient to keep the mother stable, and subtherapeutic levels of TCAs have been associated with relapse. Antidepressants should not be discontinued abruptly during pregnancy. However, as chronic use or use of high doses near to term have been associated with neonatal withdrawal symptoms, it may be appropriate to taper the dose 3 to 4 weeks before delivery. In this case, it is recommended that the pre-pregnancy dose should be resumed immediately after delivery to prevent relapse. If dose is not tapered, and use continues in the latter stages of pregnancy, particularly in the third trimester, the neonate should be observed carefully for at least 2 days after delivery for withdrawal symptoms including respiratory distress, jitteriness, irritability, tremor and feeding problems.

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

Trimipramine maleate is contraindicated in breastfeeding.

The manufacturer contraindicates the use of trimipramine during lactation. No reports of use during lactation have been located; its molecular weight and long elimination half life suggest it will be excreted in breast milk, but the effects of exposure are unknown. The LactMed database states that if trimipramine is required by the mother, it is not a reason to discontinue breastfeeding, but, due to the lack of data, other antidepressants may be preferred, particularly when nursing a newborn or premature infant.

TCAs are also acceptable with compelling indication (Schaefer, 2007). No short-term toxicity or long-term developmental effects have been demonstrated, but there is insufficient information on the long-term effects of antidepressants during breastfeeding.

Where possible, medication should be taken as a single dose before the infant's longest sleep period. Advise mothers to breastfeed immediately before a dose, and avoid breastfeeding during peak levels (i.e. 1 to 3 hours after a dose). In very young infants who feed frequently, consider substituting a bottlefeed to avoid peak levels. Avoid exposing premature or low birthweight infants to antidepressants via breast milk if at all possible. All infants should be monitored for drowsiness and other behavioural changes such as feeding difficulties, poor weight gain and restlessness.

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

Agranulocytosis
Arrhythmias
Behavioural disturbances
Blood sugar changes
Blurred vision
Bone marrow depression
Cardiac arrhythmias
Cholestatic jaundice
Confusion
Constipation
Convulsions
Delirium
Difficulty in micturition
Disturbances in accommodation
Drowsiness
Dry mouth
Dysarthria
Dyskinesia
ECG changes
Eosinophilia
Extrapyramidal effects
Fever
Galactorrhoea
Gynaecomastia
Hallucinations
Headache
Hypersensitivity reactions
Hypomania
Hyponatraemia
Inappropriate secretion of antidiuretic hormone
Increased appetite
Increased intra-ocular pressure
Increased risk of fractures
Jaundice
Leucopenia
Liver function disturbances
Mania
Movement disturbances
Nausea
Neuroleptic malignant syndrome
Paraesthesia
Paranoid delusions
Peripheral neuropathy
Photosensitivity
Postural hypotension
Purpura
Rash
Sedation
Severe hypotension
Sexual dysfunction
Suicidal tendencies
Sweating
Syncope
Tachycardia
Tardive dyskinesia
Taste disturbances
Testicular swelling
Thrombocytopenia
Tinnitus
Tremor
Urinary hesitancy
Urinary retention
Urticaria
Weight gain
Weight loss
Withdrawal symptoms

Presentation

Oral formulations of trimipramine maleate

Drugs List

Therapeutic Indications

Uses

Symptoms of depressive illness especially if sedation required

Dosage

Adults

Elderly

Contraindications

Children under 18 years
Within 2 weeks of discontinuing MAOIs
Within 2 weeks of discontinuing selegiline
Atrioventricular block
Breastfeeding
Cardiac arrhythmias
Long QT syndrome
Mania
Porphyria
Recent myocardial infarction
Severe hepatic disorder
Torsade de pointes

Precautions and Warnings

Anaesthesia
Elderly
Family history of long QT syndrome
Predisposition to epileptic disorder
Suicidal ideation
Bipolar disorder
Cardiovascular disorder
Diabetes mellitus
Electrolyte imbalance
Epileptic disorder
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of mania
History of torsade de pointes
Hyperthyroidism
Lactose intolerance
Narrow angle glaucoma
Phaeochromocytoma
Pregnancy
Prostate disorder
Psychiatric disorder
Psychosis
Renal impairment
Urinary retention

Anaesthetist should be made aware patient is taking this medication
Correct electrolyte disorders before treatment
Patients at risk of suicide should be closely supervised
Patients with diabetes may experience fluctuations in blood glucose
Advise ability to drive/operate machinery may be affected by side effects
Some formulations contain lactose
Consider monitoring ECG in patients at risk of QT prolongation
Dental check-ups advisable during long-term treatment
Monitor elderly for hyponatraemia if drowsy, confused, fitting
Monitor hepatic function on long term therapy
Monitor serum electrolytes
Advise patients/carers to seek medical advice if suicidal intent develops
Cardiac arrhythmias and severe hypotension with high dosage
Consider hyponatraemia in all patients with drowsiness/confusion/seizures
Increased risk of fractures in patients over 50 years
Life threatening arrhythmias may occur during anaesthesia and surgery
Do not withdraw this drug suddenly
Dosage reduction should be done gradually over about 4 weeks
Reduce dose in elderly
Advise patient not to take St John's wort concurrently
Patient should avoid alcohol as effect may be potentiated

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.

Pregnancy and Lactation

Pregnancy

Use trimipramine with caution in pregnancy.

Tricyclic antidepressants (TCAs), along with SSRIs, are the drug group of choice for treating depression in pregnancy. Extensive epidemiological studies have not shown evidence of a causal relationship between therapeutic doses of TCAs and an increased incidence of congenital malformations or other adverse pregnancy outcomes. However, trimipramine is not the preferred drug within the TCAs; nortriptyline, amitriptyline and imipramine have the lowest known risks during pregnancy as they are least sedative and have fewest maternal adverse effects.

Animal studies with trimipramine have found embryotoxicity and/or an increased incidence of major anomalies at 20x the human dose. This suggests low risk, but human data is too limited to assess the risk to the foetus. It is not known if trimipramine crosses the placenta, but it is likely, given its molecular weight, lipid solubility and long elimination half life. Occasional congenital malformations have been reported, but no causal relationship has been established. The use of trimipramine, despite limited data available compared to the other preferred TCAs, is not an indication for termination. Furthermore, if a pregnant patient is stable on a second-choice TCA such as trimipramine, they should not be changed to another, as this could worsen their health. However, a foetal ultrasonography should be considered.

Maternal serum levels of TCAs should be monitored, with a view to possible dose adjustment, as pharmacokinetics may be altered especially in the second and third trimesters. The usual therapeutic dose may not be sufficient to keep the mother stable, and subtherapeutic levels of TCAs have been associated with relapse. Antidepressants should not be discontinued abruptly during pregnancy. However, as chronic use or use of high doses near to term have been associated with neonatal withdrawal symptoms, it may be appropriate to taper the dose 3 to 4 weeks before delivery. In this case, it is recommended that the pre-pregnancy dose should be resumed immediately after delivery to prevent relapse. If dose is not tapered, and use continues in the latter stages of pregnancy, particularly in the third trimester, the neonate should be observed carefully for at least 2 days after delivery for withdrawal symptoms including respiratory distress, jitteriness, irritability, tremor and feeding problems.

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

Trimipramine maleate is contraindicated in breastfeeding.

The manufacturer contraindicates the use of trimipramine during lactation. No reports of use during lactation have been located; its molecular weight and long elimination half life suggest it will be excreted in breast milk, but the effects of exposure are unknown. The LactMed database states that if trimipramine is required by the mother, it is not a reason to discontinue breastfeeding, but, due to the lack of data, other antidepressants may be preferred, particularly when nursing a newborn or premature infant.

TCAs are also acceptable with compelling indication (Schaefer, 2007). No short-term toxicity or long-term developmental effects have been demonstrated, but there is insufficient information on the long-term effects of antidepressants during breastfeeding.

Where possible, medication should be taken as a single dose before the infant's longest sleep period. Advise mothers to breastfeed immediately before a dose, and avoid breastfeeding during peak levels (i.e. 1 to 3 hours after a dose). In very young infants who feed frequently, consider substituting a bottlefeed to avoid peak levels. Avoid exposing premature or low birthweight infants to antidepressants via breast milk if at all possible. All infants should be monitored for drowsiness and other behavioural changes such as feeding difficulties, poor weight gain and restlessness.

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

Agranulocytosis
Arrhythmias
Behavioural disturbances
Blood sugar changes
Blurred vision
Bone marrow depression
Cardiac arrhythmias
Cholestatic jaundice
Confusion
Constipation
Convulsions
Delirium
Difficulty in micturition
Disturbances in accommodation
Drowsiness
Dry mouth
Dysarthria
Dyskinesia
ECG changes
Eosinophilia
Extrapyramidal effects
Fever
Galactorrhoea
Gynaecomastia
Hallucinations
Headache
Hypersensitivity reactions
Hypomania
Hyponatraemia
Inappropriate secretion of antidiuretic hormone
Increased appetite
Increased intra-ocular pressure
Increased risk of fractures
Jaundice
Leucopenia
Liver function disturbances
Mania
Movement disturbances
Nausea
Neuroleptic malignant syndrome
Paraesthesia
Paranoid delusions
Peripheral neuropathy
Photosensitivity
Postural hypotension
Purpura
Rash
Sedation
Severe hypotension
Sexual dysfunction
Suicidal tendencies
Sweating
Syncope
Tachycardia
Tardive dyskinesia
Taste disturbances
Testicular swelling
Thrombocytopenia
Tinnitus
Tremor
Urinary hesitancy
Urinary retention
Urticaria
Weight gain
Weight loss
Withdrawal symptoms

Withdrawal Symptoms and Signs

Do not withdrawal this medication abruptly. Symptoms of sudden withdrawal include insomnia, irritability and excessive perspiration.
Reduce the dosage over a period of 4 weeks or longer if withdrawal symptoms emerge.
For patients that have been on long term maintenance treatment a withdrawal period of at least 6 months is recommended.

Adverse effects such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken trimipramine during the last trimester of pregnancy.

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: November 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(online) London: BMJ Group and Pharmaceutical Press Accessed on 5 November, 2014.

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

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications Accessed on 5 November, 2014.

Summary of Product Characteristics: Trimipramine 10mg tablets. Zentiva. Revised September 2012.
Summary of Product Characteristics: Trimipramine 25mg tablets. Zentiva. Revised February 2013.
Summary of Product Characteristics: Trimipramine 50mg capsules. Zentiva. Revised September 2012.

MHRA 4th February 2008
https://www.mhra.gov.uk/NewsCentre/Pressreleases/CON2033960
Last accessed: 5 November, 2014

MHRA Drug Safety Update May 2010
https://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con081866.pdf
Last accessed: 5 November, 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
Trimipramine maleate Last revised: 7 September, 2013
Last accessed: 5 November, 2014