Drugs List

Therapeutic Indications

Uses

Treatment of major depressive episodes in adults.

Administration

For oral administration

The tablets can be taken with or without food.

Contraindications

Children under 18 years

Hepatic impairment

Breastfeeding (see Lactation)

Galactosaemia

Dementia

Precautions and Warnings

Elderly (see Dosage - Elderly )

Renal impairment (see Dosage - Renal impairment )

Pregnancy (see Pregnancy )

Use with caution in patients with current or a history of bipolar disorder, mania or hypomania. Treatment should be discontinued if a patient develops manic symptoms.

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, 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.

Use with caution in patients with pre-treatment elevated transaminases. The elevation of serum transaminases have been observed in patients treated with agomelatine, which returned to normal upon discontinuation. Liver function tests should be performed in all patients at initiation of treatment, and then periodically after three weeks, six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and when clinically indicated thereafter. When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment. Any patient with increased serum transaminases should have liver function tests repeated within 48 hours. Discontinue immediately if there are signs or symptoms of potential liver injury, or if increase in serum transaminases exceeds three times the normal level. Patients should be informed of the symptoms of potential liver injury and advised to stop taking agomelatine immediately and seek urgent medical advice if these symptoms appear. Perform liver function tests regularly until serum transaminases return to normal. Where symptoms suggest dysfunction such as jaundice discontinue treatment.

Use with caution in patients with risk factors for hepatic injury e.g. obese/overweight, patients who consume substantial quantities of alcohol or who are treated concomitantly with hepatotoxic agents. Patients should be advised not to drink alcohol whilst on this medication.

Tobacco smoke induces the cytochrome P450 isoenzyme CYP1A2, by which agomelatine is metabolised. This may result in reduced agomelatine plasma level. Dosage adjustment may be required if a patient starts or stops smoking during agomelatine therapy.

Agomelatine tablets contain lactose and are therefore unsuitable for patients with glucose-galactose malabsorption syndrome or lactose intolerance.

Agomelatine may cause dizziness and somnolence, which may affect ability to drive or operate machinery.

Pregnancy and Lactation

Pregnancy

No clinical data on exposed pregnancies are available.

Animal studies (in rats and rabbits) do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development.

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 14-17 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 ).

Known human teratogen? - Unknown

Animal data - No direct or indirect harmful effects noted.

Lactation

Contraindicated in breastfeeding.

It is not known whether agomelatine is excreted into human milk, but it is excreted into the milk of lactating rats. The effects of exposure on the nursing infant have not been established. If treatment is considered necessary, the manufacturer recommends that breastfeeding should be discontinued.

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

Drug excreted in breast milk? - Unknown in humans, excreted in rats.

Drug substance licensed in infants? - No.

Side Effects

Nausea
Dizziness
Headache
Somnolence
Insomnia
Migraine
Paraesthesia
Blurred vision
Diarrhoea
Constipation
Upper abdominal pain
Hyperhidrosis
Eczema
Erythema
Back pain
Fatigue
Increase in serum ALT/AST
Hepatitis
Anxiety
Suicidal tendencies
Hypomania
Agitation
Pruritus
Mania
Drowsiness
Aggression
Nightmares
Dream abnormalities
Irritability
Restlessness
Hallucinations
Gamma glutamyl transferase (GGT) increased
Increase in alkaline phosphatase
Vomiting
Hepatic failure
Jaundice
Weight gain
Weight loss

Presentation

Tablets containing 25mg agomelatine

Drugs List

Therapeutic Indications

Uses

Treatment of major depressive episodes in adults.

Dosage

Adults

Elderly

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For oral administration

The tablets can be taken with or without food.

Contraindications

Children under 18 years

Hepatic impairment

Breastfeeding (see Lactation)

Galactosaemia

Dementia

Precautions and Warnings

Elderly (see Dosage - Elderly )

Renal impairment (see Dosage - Renal impairment )

Pregnancy (see Pregnancy )

Use with caution in patients with current or a history of bipolar disorder, mania or hypomania. Treatment should be discontinued if a patient develops manic symptoms.

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, 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.

Use with caution in patients with pre-treatment elevated transaminases. The elevation of serum transaminases have been observed in patients treated with agomelatine, which returned to normal upon discontinuation. Liver function tests should be performed in all patients at initiation of treatment, and then periodically after three weeks, six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and when clinically indicated thereafter. When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment. Any patient with increased serum transaminases should have liver function tests repeated within 48 hours. Discontinue immediately if there are signs or symptoms of potential liver injury, or if increase in serum transaminases exceeds three times the normal level. Patients should be informed of the symptoms of potential liver injury and advised to stop taking agomelatine immediately and seek urgent medical advice if these symptoms appear. Perform liver function tests regularly until serum transaminases return to normal. Where symptoms suggest dysfunction such as jaundice discontinue treatment.

Use with caution in patients with risk factors for hepatic injury e.g. obese/overweight, patients who consume substantial quantities of alcohol or who are treated concomitantly with hepatotoxic agents. Patients should be advised not to drink alcohol whilst on this medication.

Tobacco smoke induces the cytochrome P450 isoenzyme CYP1A2, by which agomelatine is metabolised. This may result in reduced agomelatine plasma level. Dosage adjustment may be required if a patient starts or stops smoking during agomelatine therapy.

Agomelatine tablets contain lactose and are therefore unsuitable for patients with glucose-galactose malabsorption syndrome or lactose intolerance.

Agomelatine may cause dizziness and somnolence, which may affect ability to drive or operate machinery.

Pregnancy and Lactation

Pregnancy

No clinical data on exposed pregnancies are available.

Animal studies (in rats and rabbits) do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development.

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 14-17 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 ).

Known human teratogen? - Unknown

Animal data - No direct or indirect harmful effects noted.

Lactation

Contraindicated in breastfeeding.

It is not known whether agomelatine is excreted into human milk, but it is excreted into the milk of lactating rats. The effects of exposure on the nursing infant have not been established. If treatment is considered necessary, the manufacturer recommends that breastfeeding should be discontinued.

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

Drug excreted in breast milk? - Unknown in humans, excreted in rats.

Drug substance licensed in infants? - No.

Effects on Ability to Drive and Operate Machinery

No studies on the effects on the ability to drive or operate machinery have been performed. Dizziness and somnolence may occur, which may affect the ability to drive or operate machinery.

Counselling

Advise patients to avoid alcohol during treatment.

Advise patients that dizziness and somnolence may occur, which may affect the ability to drive or operate machinery.

Patients and caregivers should be alerted about the need to monitor for the emergence of suicidal thoughts and behaviour and the need to seek medical advice immediately if they present.

Patients should be informed of the symptoms of potential liver injury and advised to stop taking agomelatine immediately and seek urgent medical advice if these symptoms appear.

Side Effects

Nausea
Dizziness
Headache
Somnolence
Insomnia
Migraine
Paraesthesia
Blurred vision
Diarrhoea
Constipation
Upper abdominal pain
Hyperhidrosis
Eczema
Erythema
Back pain
Fatigue
Increase in serum ALT/AST
Hepatitis
Anxiety
Suicidal tendencies
Hypomania
Agitation
Pruritus
Mania
Drowsiness
Aggression
Nightmares
Dream abnormalities
Irritability
Restlessness
Hallucinations
Gamma glutamyl transferase (GGT) increased
Increase in alkaline phosphatase
Vomiting
Hepatic failure
Jaundice
Weight gain
Weight loss

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 ).

Shelf Life and Storage

No special requirements

Further Information

Last Full Review Date: September 2012

Reference Sources

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

Summary of Product Characteristics: Valdoxan. Servier Laboratories Ltd. Revised November 2016.

MHRA 4th February 2008
https://www.mhra.gov.uk/NewsCentre/Pressreleases/CON2033960
Last accessed: April 12, 2011

Drug Safety Update Vol 6, Issue 3, October 2012
https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/index.htm
Last accessed: November 19, 2012

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 12 July 2017