COSTI Tablet Ref.[28164] Active ingredients: Domperidone

• Costi should only be taken according to the above posology (See section 4.2).
• Patients who find they have post-prandial symptoms that persist, and are having to take domperidone continuously for more than 2 weeks should be referred to their GP.
• Patients who find that their nausea and vomiting persist for more than 48 hours should be referred to their doctor.
• The patient should be advised that Costi is not recommended for the treatment of motion sickness.

Co-administration of levodopa

Although no dosage adjustment of levodopa is deemed necessary, an increase of plasma levodopa concentration (max 30-40%) has been observed when domperidone was taken concomitantly with levodopa. See section 4.5.

Use with Potent CYP3A4 Inhibitors

Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided (see section 4.5).

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.

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.

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 CYP3 A4 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 (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

There is an increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

Levodopa: Increase of plasma levels of levodopa (max 30-40%). See section 4.4.

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 antipsychotics (e.g., haloperidol, pimozide, sertindole)
• certain antidepressants (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)
• apomorphine, 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.

(See section 4.3).

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

• protease inhibitors
• systemic azole antifungals
• 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 contraindicated as it is a potent CYP3A4 inhibitor).

The above list of substances is representative and not exhaustive.

Pregnancy

There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, Costi 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.

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

The safety of domperidone 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 COSTI (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”.

Postmarketing experience

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

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

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.

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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

None known.