Motilium 10mg Film-Coated Tablets

Implementation  of PRAC recommendations following the outcome of the domperidone PSUSA (PSUSA/00001158/201611). These recommendations include updating Sections 4.3, 4.4, and 4.5 of the Summary of Product Characteristics in order to facilitate the safe use of domperidone together with apomorphine in the specific population of patients suffering of Parkinson's disease, and to update the Package leaflet accordingly.

Section 4.8 of the SPCs has been updated with the addition of the following text:

 

In 45 clinical studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin.  In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression,  hypersensitivity, lactation disorder, and irregular menstruation were also noted.

Text in red and underlined has been altered:

7.         MARKETING AUTHORISATION HOLDER

 

Johnson & Johnson (Ireland) Ltd

Airton Road

Tallaght

Dublin 24

Ireland

 

8.         MARKETING AUTHORISATION NUMBER

 

PA 330/40/2

Added/altered text has been highlighted and underlined, removed text has been highlighted and struck through:

4.4              Special warnings and precautions for use

    [...]

Cardiovascular effects:

 

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors (see section 4.5 and 4.8).

    [...]

4.5              Interaction with other Medicaments products and other forms of Interaction

 

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium.

 

Co-administration with levodopa

Although no dosage adjustment of levodopa is deemed necessary, an increase (maximum of 30% - 40%) of plasma concentration has been observed when domperidone was taken concomitantly with levodopa.

 

Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effect of Motilium.

 

Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

    [...]

          4.8       Undesirable effects

    [...]

System Organ Class	Adverse Drug Reaction Frequency
	Common	Uncommon	Not known
Immune system disorders			Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders		Loss of libido Anxiety Agitation Nervousness
Nervous system disorders		Dizziness Somnolence Headache Extrapyramidal disorder	Convulsion Restless leg syndrome*
Eye disorders			Oculogyric crisis
Cardiac disorders			Ventricular arrhythmias QTc prolongation Torsade de Pointes Sudden cardiac death (see section 4.4 and 4.5)
Gastrointestinal disorders	Dry mouth	Diarrhoea
Skin and subcutaneous tissue disorder		Rash Pruritus Urticaria	Angioedema
Renal and urinary disorders			Urinary retention
Reproductive system and breast disorders		Galactorrhoea Breast pain Breast tenderness	Gynaecomastia Amenorrhoea
General disorders and administration site conditions		Asthenia
Investigations			Liver function test abnormal Blood prolactin increased

^{*exacerbation of restless legs syndrome in patients with Parkinson’s disease}

System Organ Class	Adverse Drug Reaction Frequency
	Common	Uncommon
Psychiatric disorders		Loss of libido Anxiety
Nervous system disorders		Somnolence Headache
Gastrointestinal disorders	Dry mouth	Diarrhoea
Skin and subcutaneous tissue disorder		Rash Pruritus
Reproductive system and breast disorders		Galactorrhoea Breast pain Breast tenderness
General disorders and administration site conditions		Asthenia

Postmarketing experience

 

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported in postmarketing experience.

Immune system disorders
Not known	Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders
Not known	Agitation, nervousness
Nervous system disorders
Not known	Dizziness, convulsion, extrapyramidal disorder
Eye disorders
Not known	Oculogyric crisis
Cardiac disorders
Not Known	Ventricular arrhythmias, QTc prolongation, Torsade de Pointes sudden cardiac death, see section 4.4)
Skin and subcutaneous tissue disorders
Not known	Urticaria, angioedema
Renal and urinary disorders
Not known              Urinary retention
Reproductive system and breast disorders
Not known	Gynaecomastia, amenorrhoea
Investigations
Not known	Liver function test abnormal, blood prolactin increased

In postmarketing experience, there were no differences in the safety profile of adults and children with the exception of extrapyramidal disorder which occurred primarily in neonates and infants (up to one year of age) and other central nervous system-related effects of convulsion and agitation, which were primarily reported in infants and children.

 

An increase in the risk of serious ventricular arrhythmias and sudden cardiac death havehas been reported in some epidemiology studies (see section 4.4).

10.       Date of revision of the text

July 2015 March 2017

Shelf life reduction from 5 years to 3 years. Date of revision has been updated to reflect the approval date.



Section 4.2:

Text added:

Patients > 60 years of age:

Patients older than 60 years of age should consult a healthcare professional before taking Motilium.

Patients with severe renal impairment should be reviewed regularly (see section 5.2).

Section 4.4:

Text added:

Patients > 60 years of age:

Patients older than60 years of age should consult a healthcare professional before taking Motilium.

Added 'promptly'  to sentence: 'Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should promptly consult their physician.'

Section 4.5:

Changed from:

Concomitant use of the following substances is contraindicated

All QTc-prolonging medicinal products

o   anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)

o   anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)

o   certain antipsychotics (e.g., haloperidol, pimozide, sertindole)

o   certain antidepressants (e.g., citalopram, escitalopram)

o   certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)

o   certain antifungal agents (e.g., pentamidine)

o   certain antimalarial agents (in particular halofantrine, lumefantrine)

o   certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)

o   certain antihistaminics (e.g., mequitazine, mizolastine)

o   certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)

o   certain other medicines (e.g., bepridil, diphemanil, methadone)

(see section 4.3).

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e:

o   protease inhibitors

o   systemic azole antifungals

o   some macrolides (erythromycin, clarithromycin and telithromycin)

(see section 4.3).

TO:

Concomitant use of the following substances is contraindicated

All QTc-prolonging medicinal products (risk of torsades de points)

o   anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)

o   anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)

o   certain antipsychotics (e.g., haloperidol, pimozide, sertindole)

o   certain antidepressants (e.g., citalopram, escitalopram)

o   certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)

o   certain antifungal agents (e.g., fluconazole, pentamidine)

o   certain antimalarial agents (in particular halofantrine, lumefantrine)

o   certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)

o   certain antihistaminics (e.g., mequitazine, mizolastine)

o   certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)

o   certain other medicines (e.g., bepridil, diphemanil, methadone)

(see section 4.3).

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e:

o   protease inhibitors (e.g. ritonavir, saquinaver, telaprevir)

o   systemic azole antifungals (e.g. itraconazole, ketoconazole, posaconazole, voriconazole)

o   certain macrolides antibiotics (e.g. clarithromycin and telithromycin)

(see section 4.3).

Section 4.5

Changed from:

Motilium has no or negligible influence on the ability to drive and use machines.

TO:

Dizziness and somnolence have been observed following use of domperidone (see section 4.8) therefore, patients should be advised not to drive or use machinery or engage in other activities requiring mental alertness and coordination until they have established how Motilium affects them.

Section 4.8

‘Dizziness’ added as a side effect.



9.         Date of First Authorisation/Renewal of Authorisation

                                                      

Date of first authorisation: 5^th October 2007

Date of last renewal: 5^th October 2012

 

10.       Date of (Partial) Revision of the Text

 

            February 2015

Addition of black triangle:

 

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Section 4.1:

New indication as follows: 

 

Motilium Tablets are indicated for the relief of the symptoms of nausea and vomiting.

Section 4.2:

New dosage regimen of 3 tablets per day and should only use for 1 week:

Motilium Tablets should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.
It is recommended to take Motilium Tablets before meals. If taken after meals, absorption of the drug is somewhat delayed.
Patients should try to take each dose at the scheduled time. If a scheduled dose is missed, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.
Usually, the maximum treatment duration should not exceed one week.
Adults, and adolescents (12 years of age and older and weighing 35kg or more):
One 10mg tablet up to three times per day with a maximum dose of 30mg per day. 

 Use in children under 12 years of age (and adolescents weighing less than 35kg):
Not recommended
Hepatic Impairment
Motilium Fastmelts are contraindicated in moderate or severe hepatic impairment (see section 4.3). Dose modification in mild hepatic impairment is however not needed (see section 5.2).
Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration, the dosing frequency of Motilium Tablets should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.

Section 4.3

 

New contraindications added:

 

Domperidone is contraindicated in the following situations:

·                     Known hypersensitivity to domperidone or any of the excipients.

·                     Prolactin-releasing pituitary tumour (prolactinoma).

·                     When stimulation of the gastric motility could be harmful: gastro-intestinal haemorrhage,  mechanical obstruction or perforation.

·                     In patients with moderate or severe hepatic impairment (see section 5.2).

·                    In patients who have known existing prolongation of cardiac conduction intervals,particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure (see section 4.4).

·                    Co-administration with all QT-prolonging drugs (see section 4.5).

·                    Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects) (see  section 4.5).

 

Section 4.4

 

Additional warnings and precautions added:

 

Renal Impairment

 

The elimination half-life of domperidone is prolonged in severe renal impairment. For repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. The dose may also need to be reduced.

 

Cardiovascular effects:

 

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors (see section 4.8).

 

Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg, and patients concurrently taking QT-prolonging drugs or CYP3A4 inhibitors.

 

Domperidone should be used at the lowest effective dose in adults and children.

 

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia (see section 4.3.). Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions increasing the proarrythmic risk.

 

Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should consult their physician.

 

Patients should be advised to promptly report any cardiac symptoms

These tablets contain lactose and maybe unsuitable for patients with lactose intolerance, galactosaemia or glucose/galactose malabsorption.

 

 

Section 4.5:

 

More detail and more drugs listed:

 

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium.

 

Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effect of Motilium.

Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

 

Concomitant use of the following substances is contraindicated

All QTc-prolonging medicinal products

o        anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)

o        anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)

o        certain antipsychotics (e.g., haloperidol, pimozide, sertindole)

o        certain antidepressants (e.g., citalopram, escitalopram)

o        certain antibiotics (e.g. , erythromycin, levofloxacin, moxifloxacin, spiramycin)

o        certain antifungal agents (e.g., pentamidine)

o        certain antimalarial agents (in particular halofantrine, lumefantrine)

o        certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)

o        certain antihistaminics (e.g., mequitazine, mizolastine)

o        certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)

o        certain other medicines (e.g., bepridil, diphemanil, methadone)

(see section 4.3).

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e:

o        protease inhibitors

o        systemic azole antifungals

o        some macrolides (erythromycin, clarithromycin and telithromycin)

(see section 4.3).

 

Concomitant use of the following substances is not recommended

Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides.

(see section 4.3)

 

Concomitant use of the following substances requires caution in use

 

Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contra-indicated as it is a potent CYP3A4 inhibitor).

 

The above list of substances is representative and not exhaustive.

 

The main metabolic pathway of domperidone is through CYP3A4.  In vitro data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.  Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone’s CYP3A4 mediated first pass metabolism by these drugs.

 

With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10mg four times daily and oral erythromycin 500mg three times daily, mean QTc over the observation period was prolonged by 9.9msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the Cmax and AUC of domperidone at steady state were increased approximately three-fold in each of these interactions studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6msec (ketoconazole study) and 2.5msec (erythromycin  study), while ketoconazole monotherapy (200mg twice daily) and erythromycin monotherapy (500mg three times daily) lead to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

 

Section 4.6

 

New section on breast-feeding added:

 

Pregnancy

There are limited post marketing data on the use of domperidone in pregnant women. Therefore, Motilium Tablets should only be used during pregnancy when justified by the anticipated therapeutic benefit

Breast Feeding

Domperidone is excreted in human milk and breast-fed infants receive less than 0.1 % of the maternal weight-adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Caution should be exercised in case of QTc prolongation risk factors in breast-fed infants.

 

 

Section 4.8:

 

‘Torsades des pointes’ added as a cardiac disorder with a frequency of ‘not known’.

 

 

Also added:

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie

 

Section 4.9

 

The following text added to ‘Treatment’ section:

 

In the event of overdose, standard symptomatic treatment should be given immediately. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.  

 

Section 5.1, 5.2 and 5.3 of Section ‘Pharmacological properties’ updated with more detail.

Section 2:

Added:

 

Excipient: Each film coated tablets also contains 54.2mg of lactose monohydrate.

Section 4.2:

Take one tablet up to three times a day and one tablet at night.

changed to:

Take one tablet up to three times a day and one tablet at night (maximum   daily dose of 40mg).

Maximum duration of course of treatment 2 weeks.

changed to:

Therapy with Motilium should not exceed 2 weeks of continuous treatment without medical consultation.

Section 4.4:

Added:

Cardiovascular effects:
Motilium is not recommended for use in patients with underlying cardiac disease, without medical supervision.

Section 4.8:

Postmarketing experience
In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.

changed to:

Postmarketing experience

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported in postmarketing experience.

Extrapyramidal disorder occurs primarily in neonates and infants..

Other central nervous system-related effects of convulsion and agitation also are primarily reported in infants and children.

 

changed to:

In postmarketing experience, there were no differencs in the safety profile of adults and children with the exception of  extrapyramidal disorder which occured primarily in neonates and infants (up to one year of age) and other central nervous system-related effects of convulsion and agitation which were primarily reported in infants and children.

Section 4.9:

Symptoms:

changed to:

Symptoms and signs:

Treatment.  There is no specific antidote to domperidone; but in the event of overdose, gastric lavage as well as the administration of activated charcoal may be useful.

changed to:

Treatment.  There is no specific antidote to domperidone; but in the event of a large overdose, gastric lavage within one hour of ingestion as well as the administration of activated charcoal may be useful.

FROM

 

4.2.         Posology and Method of Administration

 

Adults and children 16 years of age and older:

Up to 10mg three times daily and at night.

 

Maximum duration of course of treatment 2 weeks.

 

Use in children under 16 years of age:

                Not recommended

TO

4.2.         Posology and Method of Administration

 

Adults and children 16 years of age and older:

Take one tablet up to three times a day and one tablet at night.

 

Do not take more than four tablets in any 24 hour period

 

Maximum duration of course of treatment 2 weeks.

 

Use in children under 16 years of age:

Not recommended

Section 4.2

A cross reference to section 4.4 added. 

Section 4.4:

Added:

Cardiovascular effects:

Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8.) The risk may be higher in patients older than 60 years or at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of Domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

 

 

Section 4.8 Undesirable Effects:

Ventricular arrhythmias and sudden cardiac death included under SOC cardiac disorders with frequency ‘unknown’. Cross reference made to section 4.4.

Section 4.5
Added:

When antacids or antisecretory drugs are used concomitantly, they should not be taken simultaneously with oral formulations of Motilium.

 

Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effect of Motilium.

Section 4.8
Updated in line with company core data sheet:

The safety of Motilium was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GERD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Motilium (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days).

Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as “Not known”.

 

System Organ Class	Adverse Drug Reaction Frequency
	Common	Uncommon
Psychiatric disorders		Loss of libido Anxiety
Nervous system disorders		Somnolence Headache
Gastrointestinal disorders	Dry mouth	Diarrhoea
Skin and subcutaneous tissue disorder		Rash Pruritus
Reproductive system and breast disorders		Galactorrhoea Breast pain Breast tenderness
General disorders and administration site conditions		Asthenia

 

 

Postmarketing experience

 

In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported. 

 

Immune system disorders
Not known	Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders
Not known	Agitation, nervousness
Nervous system disorders
Not known	Convulsion, extrapyramidal disorder
Eye disorders
Not known	Oculogyric crisis
Cardiac disorders
Very rare	Serious ventricular arrhythmias*,
Not Known	QTc prolongation
Skin and subcutaneous tissue disorders
Not known	Urticaria, angioedema
Renal and urinary disorders
Not known              Urinary retention
Reproductive system and breast disorders
Not known	Gynaecomastia, amenorrhoea
Investigations
Not known	Liver function  test abnormal, blood prolactin increased

 

*Based on epidemiology data and the estimated duration of course treatment

Extrapyramidal disorder occurs primarily in neonates and infants..

Other central nervous system-related effects of convulsion and agitation also are primarily reported in infants and children.

 

An increase in the risk of serious ventricular arrhythmias has been reported in some epidemiology studies.

Section 7:

New MAH - McNeil Healthcare (Ireland) Ltd., Airton Road, Tallaght, Dublin 24, Ireland

Section 8:

New PA no. - 823/51/2

Section 4.8

To Immune Disorders "Psychiatric system disorders: Very rare: agitation, nervousness." added

To Nervous system disorders:  2Very rare; extrapyramidal side effects, convulsion, somnolence, headache." added

"Other central nervous system-related effects of convulsion, agitation, and somnolence also are very rare and primarily reported in infants and children."

added

Section 4.9

"Overdose has been reported primarily in infants and children." added to Symptoms
"somnolence" added to Symptoms