MOTILIUM Film-coated tablet Ref.[6806] Active ingredients: Domperidone

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.

Use with apomorphine

Domperidone is contra-indicated with QT prolonging drugs including apomorphine, unless the benefit of the co-administration with apomorphine outweighs the risks, and only if the recommended precautions for co-administration mentioned in the apomorphine SmPC are strictly fulfilled. Please refer to the apomorphine SmPC.

Use in infants

Although neurological side effects are rare (see section 4.8), the risk of neurological side effects is higher in young children since metabolic functions and the blood-brain barrier are not fully developed in the first months of life. Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.

Renal impairment

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

Excipients

The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

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

Concomitant use of the following substances is contraindicated

QTc prolonging medicinal products:

• Anti-arrhythmics class IA (e.g. disopyramide, hydroquinidine, quinidine).
• Anti-arrhythmics class III (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol).
• Certain anti-psychotics (e.g. haloperidol, pimozide, sertindole).
• Certain anti-depressants (e.g. citalopram, escitalopram).
• Certain antibiotics (e.g. erythromycin, levofloxacin, moxifloxacin, spiramycin).
• Certain antifungal agents (e.g. pentamidine).
• Certain antimalarial agents (in particular halofantrine, lumefantrine).
• Certain gastro-intestinal medicines (e.g. cisapride, dolasetron, prucalopride).
• Certain antihistaminics (e.g. mequitazine, mizolastine).
• Certain medicines used in cancer (e.g. toremifene, vandetanib, vincamine).
• Certain other medicines (e.g. bepridil, diphemanil, methadone).

(see section 4.3).

• Aapomorphine, unless the benefit of the co-administration outweighs the risks, and only if the recommended precautions for co-administration are strictly fulfilled. Please refer to the apomorphine SmPC.

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

• Protease inhibitors.
• Systemic azole antifungals.
• Some macrolides (erythromycin, clarithromycin, 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.

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 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the C_max and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Pregnancy

There are limited post-marketing data on the use of domperidone in pregnant women. Studies in animals have shown reproductive toxicity at maternally toxic doses (see section 5.3). Motilium 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.

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

Tabulated list of adverse reactions

The safety of Motilium was evaluated in clinical trials and in postmarketing experience. The clinical trials included 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GORD), 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), Where frequency can not be estimated from clinical trials data, it is recorded as “Not known”.

Immune system disorders

Not known: Anaphylactic reaction (including anaphylactic shock)

Psychiatric disorders

Uncommon: Loss of libido, Anxiety

Not known: Agitation, Nervousness

Nervous system disorders

Uncommon: Somnolence, Headache

Not known: Convulsion, Extrapyramidal disorder

Eye disorders

Not known: Oculogyric crisis

Cardiac disorders (see section 4.4)

Not known: Ventricular arrhythmias, Sudden cardiac death, QTc prolongation, Torsade de Pointes

Gastrointestinal disorders

Common: Dry mouth

Uncommon: Diarrhoea

Skin and subcutaneous tissue disorder

Uncommon: Rash, Pruritus

Not known: Urticaria, Angioedema

Renal and urinary disorders

Not known: Urinary retention

Reproductive system and breast disorders

Uncommon: Galactorrhoea, Breast pain, Breast tenderness

Not known: Gynaecomastia, Amenorrhoea

General disorders and administration site conditions

Uncommon: Asthenia

Investigations

Not known: Liver function test abnormal, Blood prolactin increased

In 45 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.

Paediatric population

Extrapyramidal disorder occurs primarily in neonates and infants

Other central nervous system-related effects of convulsionand agitation alsoare primarily reported in infants and children.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Not applicable.