METOCLOPRAMIDE HYDROCHLORIDE 5 MG / ML SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Metoclopramide hydrochloride 5 mg / mL Solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL contains metoclopramide hydrochloride monohydrate equivalent to 5 mg of anhydrous metoclopramide hydrochloride.

Each ampoule of 2 mL solution contains metoclopramide hydrochloride monohydrate equivalent to 10 mg of anhydrous metoclopramide hydrochloride.

Excipient with known effect:

Each mL contains 3.34 mg or 0.145 mmol of sodium.

Each ampoule of 2 mL solution contains 6.7 mg or 0.291 mmol of sodium.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless, isotonic solution for injection.

pH: 3.0 – 5.0

4.1 Therapeutic indications

Adult population

Metoclopramide hydrochloride is indicated in adults for:

Prevention of post operative nausea and vomiting (PONV) Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting – Prevention of radiotherapy induced nausea and vomiting (RINV).

Paediatric population

Metoclopramide hydrochloride is indicated in children (aged 1 – 18 years) for: – Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option – Treatment of established post operative nausea and vomiting (PONV) as a second line option.

4.2 Posology and method of administration

The solution can be administered intravenously or intramuscularly.

Intravenous doses should be administered as a slow bolus (at least over 3 minutes).

All indications (adult patients)

For prevention of PONV a single dose of 10mg is recommended.

For the symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting and for the prevention of radiotherapy induced nausea and vomiting (RINV): the recommended single dose is 10 mg, repeated up to three times daily.

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

The injectable treatment duration should be as short as possible and transfer to oral or rectal treatment should be made as soon as possible.

All indications (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 intravenous route. The maximum dose in 24 hours is 0.5 mg / kg body weight.

Dosing table

The maximum treatment duration is 48 hours for treatment of established post operative nausea and vomiting (PONV).

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

Frequency of administration:

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).

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 may be more appropriate for administration to this population.

Paediatric population:

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Gastrointestinal haemorrhage, mechanical obstruction or gastrointestinal 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 ).

4.4 Special warnings and precautions for use

Neurological Disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. 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 6 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 in 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).

Excipients with known effect:

This medicine contains less than 1 mmol sodium (23 mg) per ampoule, that is to say essentially ‘sodium free’.

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).

Alcohol potentiates the sedative effect of metoclopramide.

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.

Ciclosporin

Metoclopramide increases ciclosporin bioavailability (Cmax by 46 % and exposure by 22 %). Careful monitoring of ciclosporin 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.

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 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)._______

* Endocrine disorders during 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, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucination, and cardiorespiratory 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 antiparkinsonian 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: drugs for functional gastrointestinal disorders, ATC code: A03FA01

Metoclopramide is a neuroleptic antagonist of dopamine. It prevents vomiting by blocking dopaminergic sites.

5.2 Pharmacokinetic properties

Distribution

Metoclopramide is vastly distributed in the tissue. The volume of distribution is 2.2 to 3.4 L / kg. Metoclopramide shows little attachment to plasma proteins. It passes through the placenta and in breast milk.

Biotransformation

Metoclopramide is poorly metabolised.

Elimination

Metoclopramide is primarily eliminated in urine, in free form or as sulfate conjugates. The elimination halflife is 5 to 6 hours. This increases in case of renal or hepatic impairment.

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

No relevant information additional to that contained elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Sodium hydroxide or hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

30 months

For single use only. After first opening of the ampoule: the product must be used immediately.

Use within 2 months after opening the protective pouch.

6.4 Special precautions for storage

Store the ampoules in the original pouch, in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Polypropylene ampoules of 2 mL solution packed in boxes of 5, 10 (2 × 5 ampoules), 20 (4 × 5 ampoules), 50 (10 × 5 ampoules) or 60 (12 × 5 ampoules).

Each 5 ampoules are overwrapped with a protective polypropylene pou­ch.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Noridem Enterprises Limited

Makariou and Evagorou,

Mitsi Building 3,

Office 115, 1065 Nicosia, Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 24598/0087

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

23/11/2021