Mygdalon/Metoclopramide 10mg

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

MYGDALON/Metoclopramide 10 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Metoclopramide Hydrochloride BP 10.00 mg equivalent to the anhydrous form. Also contains lactose, for the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adult population

Metoclopramide is indicated in adults for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV)

- Prevention of radiotherapy induced nausea and vomiting (RINV).

- Symptomatic treatment of nausea and vomting, including acute migraine induced nausea and vomiting. Metoclopramide can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine.

Diagnostic procedures:

• Radiology

• Duodenal intubation

Metoclopramide speeds up the passage of a barium meal by increasing gastric emptying time, co-ordinating peristalsis and dilating the duodenal bulb. Metoclopramide also facilitates duodenal intubation procedures.

Pediatric population

Metoclopramide is indicated in children (aged 1-18 years) for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option

Posology and method of administration

4.2

Posology

Adult patients

The recommended single dose is 10 mg, repeated up to three times daily.

The maximum recommended daily dose is 30 mg or 0.5mg/kg body weight.

The maximum recommended treatment duration is 5 days.

Prevention of delayed chemotherapy induced nausea and vomiting (CINV) (paediatric patients aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to three times daily by oral route. The maximum dose in 24 hours is 0.5mg/kg body weight.

Dosing table

Age	Body Weight	Dose	Frequency
1-3 years	10-14 kg	1 mg	Up to 3 times daily
3-5 years	15-19 kg	2 mg	Up to 3 times daily
5-9 years	20-29 kg	2.5 mg	Up to 3 times daily
9-18 years	30-60 kg	5 mg	Up to 3 times daily
15-18 years	Over 60kg	10 mg	Up to 3 times daily

The maximum treatment duration is 5 days for prevention of delayed chemotherapy induced nausea and vomiting (CINV).

Tablets are not suitable for use in children weighing less than 61 kg. Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

Special population

Elderly

In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall frailty.

Renal impairment

In patients with end stage renal disease (Creatinine clearance < 15 ml/min), the daily dose should be reduced by 75%.

In patients with moderate to severe renal impairment (Creatinine clearance 15-60 ml/min), the dose should be reduced by 50% (see section 5.2).

Hepatic impairment

In patients with severe hepatic impairment, the dose should be reduced by 50% (see section 5.2).

Other pharmaceutical forms/strengths may be more appropriate for administration to these populations.

Paediatric population

Metoclopramide is contraindicated in children aged less than 1 year (see section 4.3).

Diagnostic indications

A single dose of Metoclopramide may be given 5-10 minutes before the examination, subject to body weight consideration, (see above).

Method of administration Oral.

A minimal interval of 6 hours between two administrations is to be respected, even in case of vomiting or rejection of the dose (see section 4.4).

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section

6.1

- Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk

- Confirmed or suspected pheochromocytoma, due to the risk of severe hypertension episodes

- History of neuroleptic or metoclopramide-induced tardive dyskinesia

- Epilepsy (increased crises frequency and intensity)

- Parkinson's disease

- Combination with levodopa or dopaminergic agonists (see section 4.5)

- Known history of methaemoglobinaemia with metoclopramide or of NADH cytochrome-b5 deficiency.

- Use in children less than 1 year of age due to an increased risk of extrapyramidal disorders (see section 4.4)

Metoclopramide is contraindicated in neonates.

Metoclopramide should not be used during the first three to four days following operations such as pyloroplasty or gut anastomosis as vigorous muscular contractions may not help healing.

4.4 Special warnings and precautions for use

If vomiting persists the patient should be re-assessed to exclude the possibility of an underlying disorder, e.g. cerebral irritation.

Neurological Disorders

Extrapyramidal disorders may occur, particularly in children and young adults and/or when high doses are used (see section 4.8 Undesirable effects). These reactions occur usually at the beginning of the treatment and can occur after a single administration. Metoclopramide should be discontinued immediately in the event of extrapyramidal symptoms. These effects are generally completely reversible after treatment discontinuation, but may require a symptomatic treatment (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults).

The time interval of at least 12 hours specified in the section 4.2 should be respected between each metoclopramide administration, even in case of vomiting and rejection of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia (see section 4.8). Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Neuroleptic malignant syndrome has been reported with Metoclopramide in combination with neuroleptics as well as with Metoclopramide monotherapy (see section 4.8).Metoclopramide should be discontinued immediately in the event of symptoms of neuroleptic malignant syndrome and appropriate treatment should be initiated.

Special care should be exercised in patients with underlying neurological conditions and patients being treated with other centrally acting drugs (see section 4.3).

Symptoms of Parkinson's disease may also be exacerbated by metoclopramide.

Methaemoglobinemia

Methemoglobinemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, metoclopramide should be immediately and permanently discontinued and appropriate measures initiated (such as treatment with methylene blue).

Cardiac Disorders

There have been reports of serious cardiovascular undesirable effects including cases of circulatory collapse, severe bradycardia, cardiac arrest and QT prolongation following administration of metoclopramide by injection, particularly via the intravenous route (see section 4.8).

Special care should be taken when administering metoclopramide, particularly via the intravenous route to the elderly population, to patients with cardiac conduction disturbances (including QT prolongation), patients with uncorrected electrolyte imbalance, bradycardia and those taking other drugs known to prolong QT interval. Intravenous doses should be administered as a slow bolus (at least over 3 minutes) in order to reduce the risk of adverse effects (e.g. hypotension, akathisia).

Renal and Hepatic Impairment

In patients with renal impairment or with severe hepatic impairment a dose reduction is recommended (see section 4.2).

Metoclopramide may cause elevation of serum prolactin levels.

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

Care should be exercised when using Metoclopramide in patients with a history of atopy (including asthma) or porphyria.

Metoclopramide should not be used in the immediate post-operative period (up to 3-4 days) following pyloroplasty or gut anastomosis, as vigorous gastrointestinal contractions may adversely affect healing.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated combination

Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism (see section 4.3).

Combination to be avoided

Alcohol potentiates the sedative effect of metoclopramide.

Combination to be taken into account

Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Anticholinergics and morphine derivatives

Anticholinergics and morphine derivatives may have both a mutual antagonism with metoclopramide on the digestive tract motility.

Central nervous system depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related)

Sedative effects of Central Nervous System depressants and metoclopramide are potentiated.

Neuroleptics

Metoclopramide may have an additive effect with other neuroleptics on the occurrence of extrapyramidal disorders.

Serotonergic drugs

The use of Metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome.

Digoxin

Metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

Cyclosporine

Metoclopramide increases cyclosporine bioavailability (Cmax by 46% and exposure by 22%). Careful monitoring of cyclosporine plasma concentration is required. The clinical consequence is uncertain.

Mivacurium and suxamethonium

Metoclopramide injection may prolong the duration of neuromuscular block (through inhibition of plasma cholinesterase).

Strong CYP2D6 inhibitors

Metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. Although the clinical significance is uncertain, patients should be monitored for adverse reactions.

Metoclopramide may reduce the plasma concentration of atovaquone.

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicates no malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as other neuroleptics), in case of metoclopramide administration at the end of pregnancy, extrapyramidal syndrome in newborn cannot be excluded.

Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken.

Breastfeeding

Metoclopramide is excreted in breast milk at low level. Adverse reactions in the breast-fed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

4.7 Effects on ability to drive and use machines

Metoclopramide may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.

4.8 Undesirable effects

Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

System Organ Class	Frequency	Adverse reactions
Blood and lymphatic system disorders
	Not known	Methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4); Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing medicinal products
Cardiac disorders
	Uncommon	Bradycardia, particularly with intravenous formulation
	Not known	Cardiac arrest, occurring shortly after injectable use, and which can be subsequent to bradycardia (see section 4.4); atrioventricular block, Sinus arrest particularly with intravenous formulation; Electrocardiogram QT prolonged; Torsade de Pointes;
Endocrine disorders*
	Uncommon	Amenorrhoea, hyperprolactinaemia
	Rare	Galactorrhoea
	Not known	Gynaecomastia
Gastrointestinal disorders
	Common	Diarrhoea
General disorders and administration site conditions
	Common	Asthenia
Immune system disorders
	Uncommon	Hypersensitivity

	Not known	Anaphylactic reaction (including anaphylactic shock) particularly with intravenous formulation
Nervous system disorders
	Very common	Somnolence
	Common	Extrapyramidal disorders (particularly in children and young adults and/or when the recommended dose is exceeded, even following administration of a single dose of the drug) (see section 4.4), parkinsonism, akathisia
	Uncommon	Dystonia, dyskinesia, depressed level of consciousness
	Rare	Convulsion especially in epileptic patients
	Not known	Tardive dyskinesia which may be persistent, during or after prolonged treatment, particularly in elderly patients (see section 4.4), neuroleptic malignant syndrome (see section 4.4)
Psychiatric disorders
	Common	Depression
	Uncommon	Hallucination
	Rare	Confusional state
Vascular disorder
	Common:	Hypotension, particularly with intravenous formulation
	Not known	Shock, syncope after injectable use, acute hypertension in patients with phaeochromocytoma (see section 4.3)
* Endocrine disorders c	uring prolonged treatment in relation with hyperprolactinaemia

(amenorrhoea, galactorrhoea, gynaecomastia).

The following reactions, sometimes associated, occur more frequently when high doses are used:

- Extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonian syndrome, akathisia, even following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

- Drowsiness, decreased level of consciousness, confusion, hallucination.

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

4.9 Overdose

Symptoms

Extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucination, and cardio-respiratory arrest may occur.

Management

In case of extrapyramidal symptoms related or not to overdose, the treatment is only symptomatic (benzodiazepines in children and/or anticholinergic anti-parkinsonian medicinal products in adults).

A symptomatic treatment and a continuous monitoring of the cardiovascular and respiratory functions should be carried out according to clinical status.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Propulsives, ATC code: A03FA01

Metoclopramide acts by a blockade of dopamine receptors and an increase in prolactin secretion.

Gastric peristalsis is increased leading to an increase in the gastric-emptying rate. Duodenal peristalsis may be increased which increases intestinal transit. The resting tone of the gastro-oesophageal sphincter is also increased.

5.2 Pharmacokinetic properties

Metoclopramide is rapidly absorbed from the gastro-intestinal tract and undergoes a high degree of first-pass hepatic metabolism. It is excreted in the urine as free and as conjugated Metoclopramide and as metabolites. It is excreted in breast milk.

Renal impairment

The clearance of metoclopramide is reduced by up to 70% in patients with severe renal impairment, while the plasma elimination half-life is increased (approximately 10 hours for a creatinine clearance of 10-50 mL/minute and 15 hours for a creatinine clearance <10 mL/minute).

Hepatic impairment

In patients with cirrhosis of the liver, accumulation of metoclopramide has been observed, associated with a 50% reduction in plasma clearance.

5.3 Preclinical safety data

Not applicable

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Anhydrous Lactose Lactose

Pre-gelatinised Starch Colloidal Silicon Dioxide Magnesium Stearate

6.2 Incompatibilities

None Stated.

6.3 Shelf life

48 months all sizes.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

High density polystyrene with polythene lids and/or polypropylene containers with polythene lids and polyurethane or polythene inserts.

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000 tablets.

6.6 Special precautions for disposal

No special instructions

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited Boumpoulinas 11, 3 ^rd Floor

NICOSIA

CYPRUS P.C.1060 CYPRUS

8 MARKETING AUTHORISATION NUMBER(S)

PL 33414/0063

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/01/1983 24/02/1999

10 DATE OF REVISION OF THE TEXT

24/11/2015