MIGRAMAX 900 MG / 10 MG POWDER FOR ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Migramax 900mg/10mg Powder for oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredients                                             ­Per sachet

DL-lysine acetylsalicylate                                      1­,620 mg

equivalent to acetylsalicylic acid                               ­900 mg

Metoclopramide (INN) hydrochloride EP                     ­10.54 mg

equivalent in terms of the anhydrous substance to:              10 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Sachet containing powder for oral solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adult population

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

4.2 Posology and method of administration

Posology

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

Renal and hepatic insufficiency

Caution should be exercised in significant renal or hepatic impairment. Metoclopramide is metabolised in the liver and eliminated mainly via the kidney. A dose reduction may be necessary. (see section 5.2)

In patients with severe renal impairment (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%.

Paediatric population including adolescents

Use in children less than 1 year of age is contraindicated (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.

4.3 Contraindications

– 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 acetylsalicyclic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, 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; obstruction, haemorrhage or perforation of the GI tract.

– 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)

4.4 Special warnings and precautions for use

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 MigraMax 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 acetylsalicyclic 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, a very rare but life-threatening disease, has been observed in children and adolescents with signs of viral infections (especially chickenpox and influenza-like episodes) and who are receiving acetylsalicylic acid. Accordingly, acetylsalicylic acid should be administered in these children and adolescents only upon medical advice, when other measures have failed. In case of persistent vomiting, insufficiency of consciousness or abnormal behaviour, treatment with acetylsalicylic acid should be discontinued. 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.

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 antiinflammatory 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.

Neurological Disorders

Extrapyramidal disorders, (drowsiness, decreased level of consciousness, confusion and hallucination) 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 anti-cholinergic anti-parksonian 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 (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). Neuroleptic Malignant Syndrome (NMS), characterized by hyperthermia, muscle rigidity, extrapyramidal disorders, altered mental status and autonomic nervous instability and elevated CPK, may occur. Therefore cautions have to be taken if fever, one of the symptoms of a NMS, occurs and metoclopramide has to be stopped if a NMS is suspected.

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

Methaemoglobinaemia has been reported with metoclopramide. In case of methaemoglobinemia, MigraMax 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).

4.5 Interaction with other medicinal products and other forms of interaction

Metoclopramide-related interactions

Contraindicated combination:

Levodopa:

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

Combination to be avoided:

Alcohol:

Alcohol potentiates the sedative effect of metoclopramide.

Combinations to be taken into account:

Anticholinergics and morphine derivatives:

Anticholinergics and morphine derivatives antagonise the effects of metoclopramide on gastrointestinal motility.

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

Combination of CNS depressants with metoclopramide may result in potentiation of sedative effects.

Antipsychotics:

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

Serotonergic drugs:

The use of metoclopramide with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) may increase the risk of serotonin syndrome.

Strong CYP2D6 inhibitors such as fluoxetine:

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 decreased the bioavailability and gastric absorption of digoxin. Therefore, dose adjustment may be required. Careful monitoring of digoxin plasma concentration is required.

Ciclosporin:

Metoclopramide increases ciclosporin bioavailability. Dose adjustment may be required. In one study, dosing requirements for ciclosporin were reported to be reduced by 20% when metoclopramide was administered concomitantly. To avoid toxicity, careful monitoring of ciclosporin plasma concentration is required.

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.

– Anti-coagulants: Salicylates may enhance the effects of anti-coagulants.

– Other anti-platelet drugs: Salicylates may increase risk of bleeding with clopidogrel and ticlopidine.

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 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.

Leukotriene antagonists:

Aspirin may increase plasma concentration of zafirlukast.

Mifepristone:

Based on theoretical grounds, mifepristone may interact with salicylates.

4.6 Pregnancy and lactation

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) indicate 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.

MigraMax is not recommended during lactation because acetylsalicylic acid and metoclopramide are excreted in breast milk and adverse reactions in the breast-fed baby cannot be excluded. A decision should be made whether to discontinue breastfeeding or to abstain from Migramax treatment.

4.7 Effects on ability to drive and use machines

MigraMax may cause drowsiness. This effect can be potentiated by CNS depressants or alcohol. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

The information below lists reported adverse reactions, ranked using the following frequency classification: Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), 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, young adults and the elderly (see section 4.4).

Drowsiness, decreased level of consciousness, confusion, hallucination

–   1 The incidence of extrapyramidal symptoms in children and young adults may

increase if the metoclopramide dosage exceeds 0.5 mg/kg body weight/day.

Reactions include spasm of the facial muscles, trismus, rhythmic protrusion of the tongue, a bulbar type of speech, spasm of extra-ocular muscles including oculogyric crises, unnatural positioning of the head and shoulders and opisthotonos. There may be a generalised increase in muscle tone. The majority of reactions occur within 36 hours of starting treatment and the effects usually disappear within 24 hours of withdrawal of the drug. Should treatment of a dystonic reaction be required, a benzodiazepine or an anticholinergic anti-Parkinsonian drug may be used.

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.

4.9 Overdose

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.

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.

Overdosage 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 acetylsalicyclic 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 overdose may cause extrapyramidal disorders and drowsiness, decreased level of consciousness, confusion, hallucinations and convulsions.

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

Treatment for extrapyramidal disorders caused by metoclopramide overdose is only symptomatic (benzodiazepines in children and/or anticholinergic antiparkinsonian drugs in adults).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The pharmacological properties of this product are those of the two active ingredients ie. 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 is 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.

5.2 Pharmacokinetic properties

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 halflife 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 halflife 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 insufficiency significantly reduces the clearance of metoclopramide and increases the plasma elimination half-life.

Hepatic impairment

In patients with cirrhosis of the liver, 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.

5.3 Preclinical safety data

No data of therapeutic relevance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aspartame, glycine, lemon flavour (essential oil of lemon absorbed on a maltodextrin substrate).

6.2 Incompatibilities

No known major incompatibilities.

6.3 Shelf life

1 year

6.4 Special precautions for storage

Store at or below 25°C.

6.5 Nature and contents of container

Pack sizes:      Carton containing 2 sachets

Carton containing 6 sachets

Carton containing 20 sachets

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

6.6 Special precautions for disposal

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.

Zentiva Pharma UK Limited

12 New Fetter Lane

London

EC4A 1JP

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 17780/0552

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/03/2011