Active ingredients: Domperidone
Peridon 10 mg film-coated tablets Peridon 10 mg effervescent granules Peridon 1 mg / ml oral suspension Peridon children suppositories
Peridon package inserts are available for pack sizes:- Peridon 10 mg film-coated tablets Peridon 10 mg effervescent granules Peridon 1 mg / ml oral suspension Peridon children suppositories
- Peridon 10 mg film-coated tablets, Peridon 10 mg effervescent granules, Peridon 30 mg suppositories,
Why is Peridon used? What is it for?
This medicine belongs to the category of prokinetics.
Peridon is indicated for relieving the symptoms of nausea and vomiting.
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of the “Side Effects” section for information on how to report side effects.
Contraindications When Peridon should not be used
Peridon is contraindicated in case of:
- patients with moderate or severe hepatic impairment
- patients with known prolongation of cardiac conduction intervals, particularly the QTc interval, in patients with significant electrolyte disturbances and pre-existing heart conditions, eg congestive heart failure (see Precautions for use).
- Concomitant administration of all drugs that prolong the QT interval (see section Interactions).
- Concomitant administration of potent CYP3A4 inhibitors (regardless of their effects on QT interval prolongation) (see Interactions section).
- Known hypersensitivity to the active substance or to any of the excipients.
- Prolactin-releasing pituitary tumors (prolactinomas).
Peridon should not be used in cases where stimulation of gastric motility could be harmful: gastrointestinal bleeding, mechanical obstruction or perforation
Precautions for use What you need to know before you take Peridon
Renal impairment
The elimination half-life of domperidone is prolonged in severe renal insufficiency. drug for 7.4 to 20.8 hours, but plasma drug levels appeared lower than in healthy volunteers. Since only a very small amount of unchanged drug is excreted via the kidney, the dose of a single administration is unlikely to need correction in patients with renal insufficiency. In case of repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. It may also be necessary to reduce the dosage.
Such patients on prolonged therapy should be followed up regularly.
Cardiovascular effects
Peridon has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, very rare cases of QTc interval prolongation and torsades de pointes have been found in patients taking domperidone. These cases included patients with confounding risk factors, electrolyte disturbances and concomitant treatment which may have been contributing factors. (see section Undesirable Effects).
Epidemiological studies have shown that domperidone was associated with an increased risk of severe ventricular arrhythmias or sudden cardiac death. An increased risk has been observed in patients over 60 years of age, in patients taking daily doses greater than 30 mg and in patients taking concomitant QT-prolonging drugs or CYP3A4 inhibitors.
Domperidone should be used at the lowest effective dose.
Peridon is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly the QTc interval, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with pre-existing heart disease such as insufficiency congestive heart due to the increased risk of ventricular arrhythmia Electrolyte disturbances (hypokalaemia, hyperkalaemia hypomagnesaemia) or bradycardia are known to be conditions that increase proarrhythmic risk.
Domperidone treatment should be discontinued in the presence of signs or symptoms associated with cardiac arrhythmia and patients should consult their physician. Patients should be advised to promptly report any cardiac symptoms.
Use in patients with hepatic insufficiency
Since domperidone is predominantly metabolised in the liver, Peridon should not be used in patients with hepatic insufficiency.
Use while breastfeeding
The occurrence of adverse effects, particularly cardiac effects, cannot be excluded after exposure via breast milk. In this case, a decision must be made whether to discontinue breastfeeding or to discontinue / discontinue domperidone therapy by evaluating the benefits. breastfeeding for the baby and the benefits of therapy for the mother. (see section Special warnings)
Use in pediatrics
Neurological side effects (see section “Undesirable effects”) are rare. Since metabolic functions and the blood-brain barrier are not fully developed during the first months of life, the risk of neurological side effects is higher in young children. Therefore, it is recommended that the dose be accurately determined and strictly adhered to in neonates, infants and small pediatric patients. Overdose can cause extrapyramidal symptoms in children but other causes need to be considered.
Interactions Which drugs or foods can modify the effect of Peridon
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Domperidone is predominantly metabolised via the CYP3A4 enzyme system. Data from in vitro studies suggest that concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone. In vivo interaction studies with ketoconazole have shown marked inhibition by ketoconazole of the first pass metabolism of the domperidone mediated by cytochrome CYP3A4.
The results of this interaction study should be taken into account if domperidone is prescribed concomitantly with strong CYP3A4 inhibitors such as: ketoconazole, ritonavir and erythromycin.
Concomitant intake of the following substances is contraindicated
Medicines that prolong the QTc interval
o class IA anti-arrhythmics (e.g. disopyramide, hydroquinidine, quinidine)
o class III anti-arrhythmics (e.g. amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
o some antipsychotics (e.g. haloperidol, pimozide, sertindole)
o some antidepressants (eg citalopram, escitalopram) o some antibiotics (eg erythromycin, levofloxacin, moxifloxacin, spiramycin)
o some antifungal agents (e.g. pentamidine)
o some antimalarial agents (especially halofantrine, lumefantrine)
o some gastrointestinal medications (e.g. cisapride, dolasetron, prucalopride) or some antihistamines (e.g. mechitazine, mizolastine)
o some drugs used in the treatment of cancer (e.g. toremifene, vandetanib, vincamine)
or some other drugs (e.g. bepridil, diphemanil, methadone)
Potent CYP3A4 inhibitors (regardless of their QT-prolonging effects), for example:
or protease inhibitors
or systemic azole antifungals
o some macrolides (erythromycin, clarithromycin and telithromycin)
Concomitant use of the following substances is not recommended
Moderate inhibitors of CYP3A4, eg diltiazem, verapamil and some macrolides.
The concomitant intake of the following substances requires caution in use
Caution should be exercised in the case of drugs that induce bradycardia and hypokalaemia, as well as with the following macrolides involved in prolongation of the QT interval: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent inhibitor of CYP3A4). it is indicative and not exhaustive.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine. Peridon should only be used in pregnancy if justified by the expected therapeutic benefit.
Breastfeeding
Domperidone is excreted in human milk and breastfed infants receive less than 0.1% of the dose adjusted for maternal weight. The occurrence of adverse effects, particularly cardiac effects, cannot be excluded after exposure via breast milk. In this case, a decision must be made whether to discontinue breastfeeding or to discontinue / discontinue domperidone therapy by evaluating the benefits. of breastfeeding for the infant and the benefits of therapy for the mother. Caution should be exercised in case of risk factors that prolong the QTc interval in breastfed infants.
Effects on ability to drive and use machines
Peridon has no or negligible influence on the ability to drive or use machines.
Important information about some of the ingredients of Peridon:
In case of ascertained intolerance to sugars, contact your doctor before taking the medicine. The oral suspension contains parahydroxybenzoates which can cause allergic reactions (potentially delayed type)
Dosage and method of use How to use Peridon: Dosage
Peridon should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting. It is recommended to take Peridon oral suspension before meals. If taken after meals, the absorption of the drug is rather delayed.
Patients should try to take each dose at the correct time. If a dose is missed, it should be missed and the usual dosing schedule resumed. A double dose should not be taken to make up for a forgotten dose. Normally, the maximum treatment duration should not exceed one week.
Adults and adolescents (12 years of age or older and 35 kg or more weight)
10 ml (of 1 mg / ml oral suspension) up to three times a day for a maximum dosage of 30 ml per day.
Newborns, infants, children (less than 12 years of age) and adolescents weighing less than 35 kg
The dose is 0.25 mg / kg. This dose should be administered up to three times a day for a maximum dose of 0.75 mg / kg per day. For example, for a child weighing 10 kg, the dose is 2.5 mg and can be given three times a day for a maximum dosage of 7.5 mg per day. Oral Domperidone should be taken before meals / breastfeeding. When taken after meals, absorption of the drug is somewhat delayed.
Hepatic impairment
Peridon is contraindicated in moderate or severe hepatic impairment (see Contraindications section). However, it is not necessary to adjust the dosage in case of mild hepatic impairment
Renal impairment
Since the elimination half-life of domperidone is prolonged in the presence of severe renal impairment, the dosing frequency of Peridon should be reduced to once or twice daily depending on the severity of the impairment in case of repeated administration and may need to be reduced. the dosage.
INSTRUCTIONS FOR USE
1 The bottle has a screw cap with a child resistant opening. 2 The package contains a graduated cup and a graduated syringe for pediatric use 3 Once the bottle has been opened, the graduated syringe must be inserted into the special housing. To take the dose, turn the bottle upside down, take the exact amount of product, reposition the bottle with the syringe pointing upwards, remove the syringe and dispense the product directly from the syringe. 4 Close the bottle with the screw cap. 5 Wash the syringe thoroughly for the next use.
Overdose What to do if you have taken too much Peridon
In case of accidental ingestion / intake of an excessive dose of Peridon, notify your doctor immediately or go to the nearest hospital.
Symptoms
Symptoms of overdose may include somnolence, disorientation and extrapyramidal manifestations, especially in children.
Treatment
There is no specific antidote for domperidone but standard symptomatic treatment should be given immediately in the event of an overdose. Gastric lavage and the use of activated charcoal may therefore be useful. ECG monitoring should be performed because of the possibility of prolongation of the QT interval.
Close medical supervision and supportive therapy are recommended.
Anticholinergic and antiparkinsonian drugs may be useful in controlling extrapyramidal reactions. If you have any questions about the use of Peridon, ask your doctor or pharmacist.
Side Effects What are the side effects of Peridon
Like all medicines, Peridon can cause side effects, although not everybody gets them.
Adverse drug reactions are listed below, in order of frequency, using the following convention: very common (≥1 / 10), common (≥1 / 100, <1/10); uncommon (≥1 / 1000 to <1/100); rare (≥1 / 10,000, <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).
Immune system disorders: very rare: allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction, urticaria and angioedema.
If this happens, stop treatment immediately and contact a doctor.
Endocrine disorders: rare; increased prolactin levels.
Nervous system disorders: very rare; abnormal muscle movements or tremor, convulsion, sleepiness, headache, agitation, nervousness. The risk of abnormal muscle movements is greater in infants and young children than in adults. If this happens, stop treatment immediately and contact a doctor.
Cardiac disorders: frequency not known: ventricular arrhythmias, prolongation of the QTc interval torsades de pointes and sudden cardiac death; in the presence of these disorders, treatment should be stopped immediately.
Domperidone may be associated with an increased risk of heart rhythm disturbances and cardiac arrest. This risk may be more likely in patients over the age of 60 or taking doses greater than 30 mg per day. Domperidone should be used at the lowest effective dose in adults and children
Gastrointestinal disorders: rare; gastrointestinal disorders, including transient intestinal cramps; very rare; diarrhea.
Reproductive system and breast disorders: rare; galactorrhea, gynaecomastia, amenorrhea.
Investigations: very rare: impaired liver function. THE
Compliance with the instructions given in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system at “www.agenziafarmaco.gov.it/it/responsabili.” By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: See the expiry date printed on the package. The expiry date indicated refers to the product in intact packaging, correctly stored.
Warning: Do not use the medicine after the expiry date indicated on the package.
Special precautions for storage
Keep this medicine out of the sight and reach of children.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Composition
Peridon 1 mg / ml oral suspension
One ml contains:
- Active ingredient: domperidone 1 mg.
- Excipients: polysorbate 20, microcrystalline cellulose and carmellose, sorbitol, sodium saccharin, methyl parahydroxybenzoate, propyl parahydroxybenzoate, purified water.
PHARMACEUTICAL FORM AND CONTENT
Oral suspension: 200 ml bottle of 1 mg / ml suspension
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
PERIDON
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Peridon 10 mg film-coated tablets
One film-coated tablet contains: the active ingredient domperidone 10 mg.
Excipient with known effect: lactose.
Peridon 10 mg effervescent granules
One sachet contains: active ingredient domperidone 10 mg.
Excipients with known effects: sucrose and aspartame.
Peridon 1 mg / ml oral suspension
One milliliter of oral suspension contains: active ingredient domperidone 1 mg.
Excipients with known effects: sorbitol and para-hydroxybenzoates.
Peridon 30 mg suppositories
One suppository contains: active ingredient domperidone 30 mg.
Excipient with known effect: butyl-hydroxyanisole.
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Film-coated tablets
Effervescent granules
Oral suspension
Suppositories
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Peridon is indicated for relieving the symptoms of nausea and vomiting.
04.2 Posology and method of administration
Peridon should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.
It is recommended to take Peridon in its oral formulations (tablets, effervescent granules and oral suspension) before meals. If taken after meals, the absorption of the drug is rather delayed.
Patients should try to take each dose at the correct time. If a dose is missed, it should be missed and the usual dosing schedule should be resumed. A double dose should not be taken to make up for a forgotten dose.
As a rule, the maximum treatment duration should not exceed one week.
Dosage
Adults and adolescents (12 years of age or older and 35 kg or more weight)
Film-coated tablets
One 10 mg tablet up to three times a day for a maximum dose of 30 mg per day.
Oral suspension
10 ml (of 1 mg / ml oral suspension) up to three times a day for a maximum dosage of 30 ml per day.
10 mg effervescent granules
One sachet (containing 10 mg of domperidone per sachet) up to three times per day for a maximum dose of 3 sachets per day.
Suppositories
One 30 mg suppository inserted into the rectum twice a day.
Newborns, infants, children (less than 12 years of age) and adolescents weighing less than 35 kg
Oral suspension
The dose is 0.25 mg / kg. This dose should be administered up to three times a day for a maximum dose of 0.75 mg / kg per day. For example, for a child weighing 10 kg, the dose is 2.5 mg and can be given three times a day for a maximum dosage of 7.5 mg per day.
Oral Domperidone should be taken before meals / breastfeeding. When taken after meals, absorption of the drug is somewhat delayed.
Tablets, effervescent granules, suppositories
Due to the need for precision in dosage, the tablets, effervescent granules and suppositories are not suitable for use in children and adolescents weighing less than 35 kg.
Hepatic impairment
Peridon is contraindicated in moderate or severe hepatic impairment (see section 4.3). However, no dosage adjustment is required in case of mild hepatic impairment (see section 5.2).
Renal impairment
Since the elimination half-life of domperidone is prolonged in the presence of severe renal impairment, the dosing frequency of Peridon should be reduced to once or twice daily depending on the severity of the impairment in case of repeated administration and may need to be reduced. the dosage.
04.3 Contraindications
Domperidone is contraindicated in the following situations:
• Known hypersensitivity to the active substance or to any of the excipients.
• Prolactin-releasing pituitary tumors (prolactinomas).
• in patients with moderate or severe hepatic impairment (see section 5.2).
• in patients with known prolongation of cardiac conduction intervals, particularly the QTc interval, in patients with significant electrolyte disturbances and pre-existing cardiac conditions, eg congestive heart failure (see section 4.4).
• concomitant administration of all drugs that prolong the QTc interval (see section 4.5).
• concomitant administration of potent CYP3A4 inhibitors (regardless of their effects on QT interval prolongation) (see section 4.5).
Peridon should not be used in cases where stimulation of gastric motility could be harmful: gastrointestinal bleeding, mechanical obstruction or perforation.
04.4 Special warnings and appropriate precautions for use
Renal impairment
The elimination half-life of domperidone is prolonged in severe renal insufficiency. In patients with severe renal insufficiency (serum creatinine> 6 mg / 100 ml i and> 0.6 mmol / l) there has been an increase in the elimination half-life of the drug. 7.4 to 20.8 hours, but plasma drug levels appeared lower than in healthy volunteers. Since only a very small amount of unchanged drug is excreted via the kidney, the dose of a single administration is unlikely to need correction in patients with renal insufficiency. In case of repeated administration, the dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. It may also be necessary to reduce the dosage.
Such patients on prolonged therapy should be followed up regularly.
Cardiovascular effects
Domperidone has been associated with prolongation of the QTc interval on the electrocardiogram. During post-marketing surveillance, very rare cases of QTc interval prolongation and torsades de pointes have been found in patients taking domperidone. These cases included patients with confounding risk factors, electrolyte disturbances and concomitant treatment which may have been contributing factors. (see section 4.8).
Epidemiological studies have shown that domperidone was associated with an increased risk of severe ventricular arrhythmias or sudden cardiac death (see section 4.8). & EGRAVE; An increased risk has been observed in patients over 60 years of age, in patients taking daily doses greater than 30 mg and in patients taking concomitant QTc-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 the QTc interval, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with pre-existing heart disease such as insufficiency congestive heart disease due to the increased risk of ventricular arrhythmia (see section 4.3) Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions that increase proarrhythmic risk.
Domperidone treatment should be discontinued in the presence of signs or symptoms associated with cardiac arrhythmia and patients should consult their physician.
Patients should be advised to promptly report any cardiac symptoms.
Use in patients with hepatic insufficiency
Since domperidone is predominantly metabolised in the liver, Peridon should not be used in patients with hepatic insufficiency.
Use while breastfeeding
The occurrence of adverse effects, particularly cardiac effects, cannot be excluded after exposure via breast milk. In this case, a decision must be made whether to discontinue breastfeeding or to discontinue / discontinue domperidone therapy by evaluating the benefits. breastfeeding for the baby and the benefits of therapy for the mother (see section 4.6).
Pediatric population
Neurological undesirable effects (see section 4.8 "Possible undesirable effects") are rare. Since metabolic functions and the blood-brain barrier are not fully developed during the first months of life, the risk of neurological side effects is higher in young children. Therefore, it is recommended that the dose be accurately determined and strictly adhered to in neonates, infants and small pediatric patients (see section 4.2).
Overdose can cause extrapyramidal symptoms in children, but other causes need to be considered.
Precautions for use
& EGRAVE; the granules may appear yellowed and / or thickened; the phenomenon does not determine changes in the quality of the drug.
The film-coated tablets contain lactose and may be unsuitable for patients with lactose intolerance, glucose-galactose malabsorption.
The oral suspension contains sorbitol and may therefore not be suitable for patients with intolerance to sorbitol, furthermore the preservatives present (parahydroxybenzoates) can cause allergic reactions (potentially delayed type).
The effervescent granules contain sucrose and may be unsuitable for patients with fructose intolerance, glucose and galactose malabsorption syndrome or sucrase-isomaltase deficiency.
In the presence of diabetes or low-sugar diets, the sucrose content must be taken into account.
Suppositories contain butylhydroxyanisole which can irritate the eyes, skin and oral and nasal mucous membranes.
Use in patients with risk of hyperphenylalaninemia:
The effervescent granules contain aspartame. Do not use in patients at risk of hyperphenylalaninemia.
04.5 Interactions with other medicinal products and other forms of interaction
Domperidone is predominantly metabolised via the CYP3A4 enzyme system. Study data in vitro suggest that concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone. Single studies, in vivo, of pharmacokinetic / pharmacodynamic interaction with ketoconazole or erythromycin taken orally in healthy subjects confirmed a marked inhibition of the first pass metabolism of domperidone, via CYP3A4, by these drugs. With concomitant use of domperidone 10 mg orally four times daily and ketoconazole 200 mg twice daily, a mean QTc interval prolongation of 9.8 msec was observed, with individual changes ranging from 1.2 to 17.5 msec.
With concomitant use of domperidone 10 mg four times a day and oral erythromycin 500 mg three times a day, the mean prolongation of the QTc interval over the observation period was 9.9 msec, with individual variations ranging from 1 , 6 and 14.3 msec.
Both steady-state Cmax and AUC of domperidone were increased approximately 3-fold in each of these interaction studies.
In these studies, domperidone 10 mg monotherapy administered orally four times daily showed an increase in mean QTc interval of 1.6 msec (study with ketoconazole) and 2.5 msec (study with erythromycin), while monotherapy with ketoconazole (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) resulted in increases in the QTc interval of 3.8 and 4.9 msec, respectively, over the observation period.
Increased risk of QTc interval prolongation occurring due to pharmacodynamic and / or pharmacokinetic interactions.
Concomitant intake of the following substances is contraindicated
Medicines that prolong the QTc interval:
• class IA anti-arrhythmics (eg disopyramide, hydroquinidine, quinidine)
• class III anti-arrhythmics (eg amiodarone, dofetilide, dronedarone, ibutilide, sotalol)
• some antipsychotics (eg haloperidol, pimozide, sertindole)
• some antidepressants (for example citalopram, escitalopram)
• some antibiotics (for example erythromycin, levofloxacin, moxifloxacin, spiramycin)
• some antifungal agents (eg pentamidine)
• some antimalarial agents (in particular halofantrine, lumefantrine)
• some gastrointestinal medications (eg cisapride, dolasetron, prucalopride)
• some antihistamines (eg mechitazine, mizolastine)
• some drugs used in the treatment of cancers (for example toremifene, vandetanib, vincamine)
• some other drugs (eg bepridil, diphemanil, methadone)
(see section 4.3).
Potent CYP3A4 inhibitors (regardless of their QT-prolonging effects), for example:
• 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 inhibitors of CYP3A4, eg diltiazem, verapamil and some macrolides.
(see section 4.3).
The concomitant intake of the following substances requires caution in use
Caution should be exercised with drugs that induce bradycardia and hypokalaemia, as well as with the following macrolides involved in prolongation of the QTc interval: azithromycin and roxithromycin (clarithromycin is contraindicated as it is a potent inhibitor of CYP3A4).
The above list of substances is indicative and not exhaustive.
04.6 Pregnancy and lactation
Pregnancy
There are few post-marketing data on the use of domperidone in pregnant women. A study in rats showed reproductive toxicity at a high dose, toxic to the mother. The potential risk to humans is unknown. Therefore, Peridon should only be used in pregnancy if justified by the expected therapeutic benefits.
Breastfeeding
Domperidone is excreted in human milk and breastfed infants receive less than 0.1% of the dose adjusted for maternal weight. The occurrence of adverse effects, particularly cardiac effects, cannot be excluded after exposure via breast milk. In this case, a decision must be made whether to discontinue breastfeeding or to discontinue / discontinue domperidone therapy by evaluating the benefits. of breastfeeding for the infant and the benefits of therapy for the mother. Caution should be exercised in case of risk factors that prolong the QTc interval in breastfed infants.
04.7 Effects on ability to drive and use machines
Peridon has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
Adverse drug reactions are listed below, in order of frequency, using the following convention: very common (≥1 / 10), common (≥1 / 100,
Disorders of the immune system: very rare; allergic reactions including anaphylaxis, anaphylactic shock, anaphylactic reaction, urticaria and angioedema.
Endocrine pathologies: rare; increased prolactin levels.
Nervous system disorders: very rare; extrapyramidal effects, convulsions, drowsiness, headache, agitation, nervousness.
Cardiac pathologies: frequency not known; ventricular arrhythmias, QTc interval prolongation torsades de pointes and sudden cardiac death (see section 4.4).
Gastrointestinal disorders: rare; gastrointestinal disorders, including transient intestinal cramps; very rare; diarrhea.
Skin and subcutaneous tissue disorders: very rare; hives, itching, skin rash.
Reproductive system and breast disorders: rare; galactorrhea, gynaecomastia, amenorrhea.
Diagnostic tests: very rare; abnormal liver function test.
Since the pituitary is located outside the blood brain barrier, domperidone can cause increased prolactin levels. In rare cases, this hyperprolactinaemia can cause neuro-endocrine side effects such as galactorrhea, gynaecomastia and amenorrhea.
Extrapyramidal side effects are very rare in infants and young children and exceptional in adults. These effects disappear spontaneously and completely upon discontinuation of treatment.
Other central nervous system side effects such as seizures, agitation and sleepiness are very rare and reported mainly in infants and children.
See section 4.4 Special warnings and precautions for use.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms
Symptoms of overdose may include somnolence, disorientation and extrapyramidal manifestations, especially in children.
Treatment
There is no specific antidote to domperidone but in the event of an overdose, standard symptomatic treatment should be given immediately. Gastric lavage and the use of activated charcoal may therefore be helpful. ECG monitoring should be performed because of the possibility of QT interval prolongation.
Close medical supervision and supportive therapy are recommended.
Anticholinergic and antiparkinsonian drugs may be useful in controlling extrapyramidal reactions.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Prokinetics
ATC code: A03F A 03
Domperidone is a dopamine antagonist with antiemetic properties. Domperidone does not easily cross the blood brain barrier. In patients treated with domperidone, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. The antiemetic effect of domperidone may result from the combination of peripheral (gastrokinetic) effects and antagonism of the dopaminergic receptors in the "chemoreceptor trigger zone", located outside the blood brain barrier in the postrema area. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopaminergic receptors.
Studies in humans have shown that oral domperidone increases lower esophageal sphincter pressure, improves anthroduodenal motility and accelerates gastric emptying. It has no effect on gastric secretion.
In accordance with ICHâE guidelines. "E14 a thorough QT interval study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with a domperidone dosage of up to 80 mg per day in doses of 10 or 20 mg administered 4 times a day. This study identified a maximum difference in corrected QT interval (QTc) between domperidone and placebo in LS mean (Least Squares) in the change from baseline of 3.4 msec for 20 mg of domperidone administered 4 times daily on Day 4. The two-way confidence interval of 90% (1.0 to 5.9 msec) did not exceed 10 msec. No relevant effects on the interval were observed in this study. QTc when domperidone was given at a dose up to 80 mg / day (e.g. more than twice the maximum recommended dose).
However, two previous drug interaction studies have shown evidence of QTc interval prolongation when domperidone was given as monotherapy (10 mg 4 times a day). The maximum time-matched mean difference in Fridericia corrected QT interval (QTcF) between domperidone and placebo was 5.4 msec (95% CI: -1.7 to 12.4) and 7.5 msec (95 CI), respectively. %: 0.6 to 14.4).
05.2 "Pharmacokinetic properties
Absorption
Domperidone is rapidly absorbed following oral administration, with peak plasma concentrations occurring approximately 1 hour after dosing. Time to peak absorption is slightly delayed and AUC is somewhat increased when the drug is taken orally after a meal. Domperidone Cmax and AUC values increased proportionally with doses ranging from 10 mg to 20 mg. An accumulation of 2 or 3 times the AUC of domperidone was observed with repeated dosing four times daily (every 5 hours) of domperidone for 4 days.
Although the bioavailability of domperidone is increased in normal subjects when taken after a meal, patients with gastrointestinal disorders should take domperidone 15 - 30 minutes before a meal. The reduction of gastric acidity alters the absorption of domperidone. Oral bioavailability is reduced by prior concomitant administration of cimetidine and sodium bicarbonate.
Distribution
Oral domperidone does not show accumulation or metabolic self-induction phenomena; 90 minutes after administration, the peak plasma level, after two weeks of oral administration at the daily dose of 30 mg, was 21 ng / ml, therefore it was almost comparable to that of 18 ng / ml obtained after the first dose.
Domperidone is 91-93% bound to plasma proteins.
Distribution studies, performed with radiolabelled drug in animals, revealed "wide tissue distribution but low brain concentrations. Small amounts of the drug cross the placenta in rats."
Biotransfomation
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation.
Metabolism Studies in vitro with diagnostic inhibitors indicate that CYP3A4 is the form of cytochrome P-450 most involved in the N-dealkylation of domperidone, while CYP3A4, CYP1A2 and CYP2E1 are involved in the aromatic hydroxylation of domperidone.
Elimination
Urinary and faecal excretion amount to 31% and 66% of the oral dose, respectively.
The proportion of unchanged drug excreted is small (10% of faecal excretion and approximately 1% of urinary excretion).
The plasma half-life after a single oral dose is 7 - 9 hours in healthy volunteers but is prolonged in patients with severe renal insufficiency.
Hepatic impairment
In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh classification B), the AUC and C of domperidone are 2.9- and 1.5-fold higher, respectively, than in healthy subjects.
The unbound fraction is increased by 25% and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a slightly lower systemic exposure than healthy subjects based on Cmax and AUC values, without no changes in protein binding or terminal half-life. Subjects with severe hepatic impairment have not been studied. Domperidone is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).
Renal impairment
In subjects with severe renal impairment (creatinine clearance
Since a very small amount of unchanged drug is excreted (approximately 1%) via the kidneys, it is unlikely that the dose of a single administration will need to be adjusted in patients with renal insufficiency.
However, in case of repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the disorder and the dosage may need to be reduced.
05.3 Preclinical safety data
Electrophysiological studies in vitro and in vivo indicate a moderate overall risk of QTc interval prolongation in humans for domperidone. In experiments in vitro on isolated cells transfected with hERG and on isolated myocytes from guinea pigs, exposure ratios ranged from 26 to 47 times, based on IC50 values that inhibit currents through IKr ion channels compared to free plasma concentrations in humans after administration of the maximum daily dose of 10 mg administered 3 times daily. The safety margins for prolonging the duration of action potential in in vitro experiments on isolated cardiac tissues were 45 times higher than the free plasma concentrations in humans at the dose daily maximum (10 mg administered 3 times daily). The safety margins in in vitro proarctimic models (isolated Langendorff perfused heart) were 9 to 45 times higher than the free plasma concentrations in humans at the maximum daily dose ( 10 mg administered 3 times a day). In models in vivo the no-effect levels for prolonged corrected QT interval (QTc) in dogs and induction of arrhythmias in a rabbit model sensitized for torsades de pointes were more than 22-fold and 435-fold, respectively, above the free plasma concentrations in "man at the maximum daily dose (10 mg administered 3 times daily). In the model with anesthetized guinea pig following intravenous infusions, there was no effect on the corrected QT interval (QTc) at total plasma concentrations of 45.4 ng. / ml, which are 3 times higher than the total plasma levels in humans at the maximum daily dose (10 mg administered 3 times a day). The relevance of this latest study to humans following exposure to administered domperidone orally is uncertain.
In the presence of inhibition of metabolism by CYP3A4 the free plasma concentrations of domperidone can triple.
At a high maternal toxic dosage (more than 40 times the recommended human dose) teratogenic effects were seen in the rat. No teratogenicity was observed in mice and rabbits.
In lactating female rats, the drug is excreted in breast milk (mainly as metabolites: peak concentrations of 40 and 800 ng / ml after oral and intravenous administration of a dose of 2.5 mg / kg, respectively).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Film-coated tablets: lactose hydrate, corn starch, microcrystalline cellulose, pregelatinized starch, hydrogenated vegetable oil, povidone, sodium lauryl sulfate, magnesium stearate; Coating: hypromellose, sodium lauryl sulfate.
Effervescent granules: aspartame, povidone, tartaric acid, flavors, sodium bicarbonate, sucrose.
Oral suspension: polysorbate 20, microcrystalline cellulose and carmellose, sorbitol, sodium saccharin, methyl parahydroxybenzoate, propyl parahydroxybenzoate, purified water.
Suppositories: tartaric acid, macrogol 400, macrogol 1000, macrogol 4000, butyl-hydroxyanisole.
06.2 Incompatibility
None known.
06.3 Period of validity
Peridon 10 mg film-coated tablets: 3 years.
Peridon 10 mg effervescent granules: 3 years.
Peridon 1 mg / ml oral suspension: 3 years.
Peridon 30 mg suppositories: 3 years.
06.4 Special precautions for storage
Film-coated tablets and effervescent granules: store at a temperature not exceeding 25 ° C in the original packaging to protect the product from humidity.
Oral suspension: no particular storage conditions.
Suppositories: Do not store above 30 ° C
06.5 Nature of the immediate packaging and contents of the package
Peridon 10 mg film-coated tablets: box of 30 tablets in PVC / Al blister.
Peridon 10 mg effervescent granules: box of 30 sachets.
Peridon 1 mg / ml oral suspension: bottle of 200 ml - child resistant closure.
Peridon 30 mg suppositories: 6 suppositories in PVC / PE blisters.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Italchimici S.p.A.
Via Pontina n ° 5, Km 29
00040 Pomezia (RM)
08.0 MARKETING AUTHORIZATION NUMBER
Peridon 10 mg film-coated tablets - box of 30 tablets AIC n. 024309039
Peridon 10 mg effervescent granules - box of 30 sachets AIC n. 024309130
Peridon 1 mg / ml oral suspension - 200 ml bottle AIC n. 024309142
Peridon 30 mg suppositories - 6 suppositories AIC n. 024309066
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First Authorization:
Peridon 10 mg film-coated tablets: 06.06.81
Peridon 10 mg effervescent granules: 01.03.89
Peridon 1 mg / ml oral suspension: 06.06.81
Peridon 30 mg suppositories: 22.04.82
Renewal of the Authorization: 31.05.2010
10.0 DATE OF REVISION OF THE TEXT
January 2015
