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.
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.
- Hypersensitivity to the active substance or any of the excipients listed in 6.1.
- Gastrointestinal haemorrhage, mechanical obstruction or gastrointestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk.
- A history of neuroleptic or metoclopramide-induced tardive dyskinesia.
- Epilepsy (increased crises frequency and intensity)
- Parkinson's disease
- Confirmed or suspected phaeochromocytoma due to the risk of severe hypertension episode.
- Combination with levodopa or dopaminergic agonists.
- 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
- 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 Primavera-N-induced tardive dyskinesia
- Epilepsy (increased crises frequency and intensity)
- Parkinson's disease
- Combination with levodopa or dopaminergic agonists
- Known history of methaemoglobinaemia with Primavera-N or of NADH cytochrome-b5 deficiency.
- Use in children less than 1 year of age due to an increased risk of extrapyramidal disorders
No particulars.
None known.
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).
| Systeme 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 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 ; 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 | 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) , 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 , Neuroleptic malignant syndrome | |
| 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 , Transient increase in blood pressure | |
* 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.
- 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.
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 Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulfur-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 ; 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) , 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 , Neuroleptic malignant syndrome | |
| 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 Transient increase in blood pressure | |
* 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.
- 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
No abnormalities have been found in animal studies to indicate a safety risk in humans. This is based on data from pharmacological studies relating to safety, and data on toxicity following repeated administration, genotoxicity, carcinogenicity and reproductive toxicity.
Not applicable.
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 vomiting, 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.
Paediatric 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
Adult population
Primavera-N 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 vomiting, including acute migraine induced nausea and vomiting. Primavera-N can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine.
Paediatric population
Primavera-N 10mg tablets are indicated in children (aged 15-18 years) for:
- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option
Metoclopramide is a substituted benzamide. It is used among other things because of its anti-emetic properties. The anti-emetic effect is the result of two mechanisms of action involving the central nervous system:
- antagonism of the dopaminergic D2 receptors in the chemoreceptor trigger zone and in the vomiting centre of the medulla which is affected in apomorphine-induced vomiting;
- antagonism of the serotoninergic 5HT3 receptors and agonist effect on the 5HT4 receptors which are affected in chemotherapy-induced vomiting.
In addition to the central action, metoclopramide has a stimulant effect on gastrointestinal motility via a peripheral mechanism of action. There is an antidopaminergic effect and potentiation of the effect of acetylcholine. This causes accelerated emptying of the stomach and there is an increase in the pressure exerted by the lower oesophageal sphincter. Metoclopramide has no effect on gastric secretions.
Primavera-N hydrochloride is an anti-emetic and an accelerator of gastric emptying.
Following oral administration the relative bioavailability compared with intravenous administration is 60 to 100%. Peak plasma concentrations are reached within 0.5 to 2 hours.
The distribution volume is 2-3 l/kg; 13-22% is bound to plasma proteins. Metoclopramide is excreted primarily in the urine, both in unchanged form and in sulfate or glucuronide conjugate form. The principal metabolite is an N-4 sulphur conjugate.
The plasma elimination half-life is 5 to 6 hours, irrespective of the route of administration.
Special patient populations
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.
Renal impairment
The clearance of Primavera-N 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 Primavera-N has been observed, associated with a 50% reduction in plasma clearance.
Special warnings
Neurological Disorders
Extrapyramidal disorders may occur, particular 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).
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. 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. 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
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 dministration of metoclopramide by injection, particularly via the intravenous route.
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.
Primavera-Ne tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not use this medicine.
Neurological Disorders
Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used.
Prolonged treatment with Primavera-N may cause tardive dyskinesia, potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia. Treatment must be discontinued if clinical signs of tardive dyskinesia appear.
Neuroleptic malignant syndrome has been reported with Primavera-N in combination with neuroleptics as well as with Primavera-N monotherapy. Primavera-N 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
Symptoms of Parkinson's disease may also be exacerbated by Primavera-N.
Methaemoglobinemia
Methemoglobinemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, Primavera-N 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 Primavera-N by injection, particularly via the intravenous route.
Special care should be taken when administering Primavera-N, 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.
Contains lactose:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Metoclopramide may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.
Primavera-N may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery.
Posology
Adult population
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 0.5 mg/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 30 kg.
Other pharmaceutical forms/strengths may be more appropriate for administration to this population.
Method 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.
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%.
Hepatic impairment:
In patients with severe hepatic impairment, the dose should be reduced by 50%.
Paediatric population
Metoclopramide is contraindicated in children aged less than 1 year.
All indications (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.
Paediatric patients aged 15-18 years
Prevention of delayed chemotherapy induced nausea and vomiting (CINV)
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 0.5 mg/kg body weight.
Dosing table
| Age | Body Weight | Dose | Frequency |
| 15-18 years | Over 60kg | 10mg | 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 61kg.
Other pharmaceutical forms/strengths may be more appropriate for administration to this population.
Method 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.
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%.
Hepatic impairment:
In patients with severe hepatic impairment, the dose should be reduced by 50%.
Paediatric population
Primavera-N is contraindicated in children aged less than 1 year.
No special requirements.
Not applicable.
Administrative data
