Migramax 900mg/10mg Powder for Oral Solution

Adult population

MigraMax is indicated for the treatment of migraine-associated symptoms such as headache, nausea and vomiting.

Adults (aged 18 years and older)

One sachet should be taken at the first warning of a migraine attack. A second sachet may be taken two hours later if the symptoms have not resolved. Do not exceed three sachets in a 24 hour period.

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).

Paediatric population including adolescents

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

Use in children and adolescents between the ages of 1 and 18 years is not recommended.

Treatment should not exceed 3 months due to the presence of metoclopramide (see sections 4.4 and 4.8)

Method of administration

For oral administration only.

MigraMax must be dissolved completely in some water before taking.

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

• Patients with pre-existing mastocytosis, in whom the use of acetylsalicylic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypertension, tachycardia and vomiting). In these patients, aspirin has the potential to induce anaphylaxis either on its own or in combination with food and/or exercise.

• 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 crisis 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.

• Active, chronic or recurrent gastric or duodenal ulcers.

• Congenital or acquired bleeding disorders

• Third trimester of pregnancy.

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

• Patients with severe hepatic insufficiency

• Patients with severe renal insufficiency (CrCL <30 ml/min)

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

As salicylates may induce asthma attacks in susceptible individuals MigraMax should be avoided in patients at risk of developing sensitivity reactions. These include individuals with asthma or rhinitis, a history of atopy or nasal polyps, and also patients who have been sensitive to other salicylates or NSAIDs.

Care should be exercised when using MIGAMAX SACHETS in patients with a history of porphyria.

Use with caution in patients with a history of gastroduodenal ulcer or GI haemorrhage, or with mild and moderate hepatic impairment, gout or menorrhagia.

In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section 4.5).

Care should be taken in patients using intra-uterine contraceptive devices and patients who have a high alcohol intake. Alcohol may increase the risk of gastrointestinal injury when taken with acetylsalicylic acid. The clinical significance of this interaction is unclear but those who drink more than the recommended daily limits of alcohol may be at greater risk (it may lead to bleeding from the stomach).

There is a possible association between aspirin and Reye's syndrome when given to children with a fever. Reye's syndrome is a very rare disease which affects the brain and liver, and can be fatal. For this reason, aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).For this reason aspirin should not be given to children under 12 years and should be avoided up to and including 16 years of age if feverish.

MigraMax is contraindicated in patients under 18 years of age.

Concomitant treatment with levothyroxine and salicylates should be avoided (see section 4.5).

This drug must be administered under close medical supervision in patients with glucose-6 phosphate dehydrogenase deficiency due to risk of haemolysis (see section 4.8).

For acetylsalicylic acid > 500mg/day:

There is some evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Cases of acute renal failure after initiation of high dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients treated with tenofovir disoproxil fumarate and with risk factors for renal dysfunction. If tenofovir disoproxil fumarate is co-administered with an NSAID, renal function should be monitored adequately.

As total clearance of metoclopramide is reduced and elimination prolonged in patients with renal failure use in patients with significant degrees of renal impairment should be approached with caution.

Metoclopramide may induce an acute hypertensive response in patients with phaeochromocytoma.

Due to the risk of tardive dyskinesia with metoclopramide, treatment should not exceed 3 months (see also sections 4.2 and 4.8).

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.

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

Metoclopramide is not recommended in epileptic patients as benzamides may decrease the epileptic threshold.

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.

The management of NMS should include:

1) immediate discontinuation of the product,

2) intensive symptomatic treatment and medical monitoring and

3) treatment of any concomitant serious medical problems for which specific treatments are available.

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.

Methaemoglobinaemia

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-related interactions

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.

Combinations 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 (CNS) depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related)

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

Antipsychotics

Combination of antipsychotics with metoclopramide may result in potentiation of extrapyramidal effects.

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.

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 Due to the promotion of gastric emptying and normal peristalsis (see section 5.1) caused by metoclopramide, the absorption of certain drugs may be modified.

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).

Alcohol

Alcohol potentiates the sedative effect of metoclopramide

Salicylate-related interactions

Drugs associated with bleeding risk

There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of drugs associated with bleeding risk should be undertaken with caution:

Nicorandil

In patients concomitantly receiving nicorandil and NSAIDs including ASA and LAS, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section 4.4).

Metamizole

Metamizole may reduce the effect of acetylsalicylic acid (aspirin) on platelet aggregation, when taken concomitantly. Therefore, this combination should be used with caution in patients taking low dose aspirin for cardioprotection.

Acetazolamide

Caution is recommended when co-administering salicylates with acetazolamide as there is an increased risk of metabolic acidosis.

Antimetabolites

Salicylates may enhance the effects of methotrexate.

Oral anti-diabetic agents

Salicylates may enhance the effects of oral anti-diabetic agents.

Levothyroxine

Salicylates, specifically at doses greater than 2.0 g/day, may inhibit binding of thyroid hormones to carrier proteins and thereby lead to an initial transient increase in free thyroid hormones, followed by an overall decrease in in total thyroid hormone levels. Thyroid hormone levels should be monitored (see section 4.4).

Anti-epileptics

Salicylates may enhance the effects of phenytoin, sodium valproate.

Valproic acid

The concomitant administration of salicylates and valproic acid may result in decreased valproic acid protein binding and inhibition of valproic acid metabolism resulting in increased serum levels of total and free valproic acid.

Alcohol

Alcohol may increase the risk of gastrointestinal injury when taken with acetylsalicylic acid.

The clinical significance of this interaction is unclear but those who drink more than the recommended daily limits of alcohol may be at greater risk (it may lead to bleeding from the stomach).

Tenofovir

Concomitant administration of tenofovir disproxil fumarate and NSAIDs may increase the risk of renal failure.

Varicella vaccine

It is recommended that patients not be given salicylates for an interval of six weeks after receiving the varicella vaccine. Cases of Reye's syndrome have occurred following the use of salicylates during varicella infections.

Immunomodulating agents

Salicylates may inhibit the action of alpha interferon

Salicylates may interact with other NSAIDs, antacids and glucorticosteroids, which may lower blood salicylate concentration during treatment and result in high levels when treatment is stopped.

The effects of diuretics and uricosurics may also be affected by salicylates.

Other anti-platelet drugs

Salicylates may increase risk of bleeding with clopidogrel and ticlopidine.

Leukotriene antagonists

Aspirin may increase plasma concentration of zafirlukast

Mifepristone

Based on theoretical grounds, mifepristone may interact with salicylates.

Metoclopramide

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 newborns cannot be excluded. Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken.

Due to pharmacological properties, as with other benzamides, in instances of metoclopramide administration before delivery, extrapyramidal disorders in newborns cannot be excluded.

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.

Acetylsalicylic acid

Pregnancy

Although teratogenic effects of acetylsalicylic acid have been recorded in animals, no such effects have been observed in humans.

No teratogenic effects have been observed with metoclopramide: data on pregnant patients (> 1000) indicate no malformative nor foeto/neonatal toxicity during 1rst trimester of pregnancy. A limited amount of data on pregnant patients (> 300) indicates no neonatal toxicity in other trimesters. Animal studies do not indicate reproductive toxicity.

In the third trimester, the use of prostaglandin synthesis inhibitors such as acetylsalicylic acid may expose the foetus to premature closure of the ductus arteriosus. MigraMax is therefore contra-indicated during the third trimester. Like all drugs avoid use in the first and second trimester unless the physician believes the benefits outweigh the risk.

Breastfeeding

MigraMax is not recommended during lactation because acetylsalicylic acid is excreted in breast milk and adverse reactions in the breast-fed baby cannot be excluded.

A decision should be made whether to discontinue breast-feeding or to abstain from Migramax treatment.

MigraMax may cause drowsiness, dizziness, dyskinesia and dystonias which could affect the vision and also interfere with the ability to drive and operate machinery. This effect can be potentiated by CNS depressants or alcohol.

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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In cases of overdose, toxic reactions are mainly ascribable to aspirin.

Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (95.1mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.

Acetylsalicylic acid symptoms

Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases. A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier. Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Overdose with salicylates, particularly in young children, can result in severe hypoglycaemia and potentially fatal poisoning.

Non-cardiogenic pulmonary oedema can occur with acute and chronic acetylsalicylic acid overdose (see section 4.8).

Management

Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema. Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations > 700 mg/L (5.1 mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

Metoclopramide symptoms

Metoclopramide overdose may cause extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucinations, convulsions and cardio-respiratory arrest may occur.

Decreased levels of consciousness, confusion, hallucinations resolve after metoclopramide withdrawal.

Treatment for extrapyramidal disorders caused by metoclopramide, whether related or not to overdose, 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.

The pharmacological properties of this product are those of the two active ingredients i.e. an analgesic and an antiemetic.

Acetylsalcylic acid has analgesic, antipyretic and anti-inflammatory properties. It inhibits prostaglandin synthesis so that the prostaglandin-induced sensitivity of peripheral nerve endings to kinins and other mediators of pain and inflammation are reduced. Acetylsalicylic acid also exerts a powerful inhibition on platelet aggregation by blocking thromboxane A2 synthesis in the platelets.

Metoclopramide is an effective anti-emetic, although its exact mechanism(s) of action is not fully established. It is a cholinergic agonist acting peripherally to enhance the action of acetylcholine at muscarinic synapses and in the CNS by blocking dopamine receptors in the chemoreceptor trigger zone for vomiting.

Local effects include the promotion of gastric emptying and normal peristalsis, impairment of which are a common feature of migraine attacks.

Lysine acetylsalicylate

Absorption of lysine acetylsalicylate as a solution is rapid in healthy subjects. Lysine acetylsalicylate dissociates into lysine and acetylsalicylic acid which is rapidly hydrolysed to salicylic acid. The plasma peak of acetylsalicylic acid is achieved within 20 minutes.

Plasma salicylates are essentially bound to plasma proteins and are converted to inactive metabolites in the liver. Salicylic acid and its metabolites are excreted via the kidneys. Clearance increases with increasing urinary pH. The elimination half-life of salicylic acid is dose-dependent owing to the saturable nature of salicylic acid conjugation and ranges from as little as 2 hours after a single dose of 500 mg, lengthening to as long as 20 hours in overdose.

Metoclopramide

The plasma peak of metoclopramide is reached within an average time of 40 minutes following oral administration. Peak plasma concentrations are 32 and 70 g/L for 10 and 20 mg doses.

Bioavailability is 80% following oral administration. Inter-individual variations are related to a 20% first-pass effect. Metoclopramide is rapidly and extensively distributed in tissues. The volume of distribution is 2.2 - 3.4 l/kg. Metoclopramide has a low degree of binding to plasma proteins (30%). The plasma elimination half-life of metoclopramide is 5 - 6 hours. Total clearance is 0.4 - 0.7 l/min.

Metoclopramide is only partially metabolised in humans; urinary excretion occurs essentially as the unchanged and sulphoconjugated compounds (50% of the dose administered).

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.

Hepatic impairment

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

Combination

When administered as an oral solution, lysine acetylsalicylate and metoclopramide are rapidly absorbed.

In subjects not suffering from migraine, plasma concentrations of total salicylates, acetylsalicylic acid and metoclopramide do not differ from those recorded following both drugs administered singly.

The elimination half-life of salicylates and metoclopramide is unaffected in subjects suffering from migraine receiving the two drugs in combination compared with normal subjects.

No data of therapeutic relevance.

Aspartame

Glycine

Lemon flavour (essential oil of lemon absorbed on a maltodextrin substrate)

No known major incompatibilities

1 year

Store at or below 25^oC

MigraMax is packaged in sachets made of a paper-polyethylene-aluminium complex, containing one unit dose and heat-sealed.

Consult the patient leaflet before use.

Do not use after the stated expiry date on the sachet or carton.

To be taken orally when the powder is completely dissolved.