4.1. Therapeutic indications

Panmigrol Migraine Pain Relief is indicated in adults for the acute treatment of headache and of migraine attacks with or without aura.

4.2. Posology and method of administration

Posology

Adults (18 years and older)

For headache:

The usual recommended dosage is 1 tablet; an additional tablet can be taken, with 4 to 6 hours between doses. In case of more intense pain, it is possible to take 2 tablets. If needed, additional 2 tablets can be taken, with 4 to 6 hours between doses.

Panmigrol Migraine Pain Relief is intended for episodic use, up to 4 days for headache.

For migraine:

Take 2 tablets when symptoms appear. If needed additional 2 tablets can be taken, with 4 to 6 hours between doses.

Panmigrol Migraine Pain Relief is intended for episodic use, up to 3 days for migraine.

For both headache and migraine, intake must be limited to 6 tablets in 24 hours. The medicinal product must not be used for a longer period or at a higher dosage without first consulting a doctor. (see section 4.4).

Drink a full glass of water with each dose.

Children and adolescents (under 18 years of age)

Safety and efficacy of Panmigrol Migraine Pain Relief in children and adolescents have not been evaluated. Use of Panmigrol Migraine Pain Relief in children and adolescents is therefore not recommended (see section 4.4).

Elderly

Based on general medical considerations, caution should be exercised in the elderly, particularly in elderly patients with low body weight.

Hepatic and renal impairment

The effect of hepatic or renal disease on the pharmacokinetics of Panmigrol Migraine Pain Relief has not been evaluated. Due to the mechanism of action of acetylsalicylic acid and paracetamol, this could enhance the renal or hepatic impairment. Thus, Panmigrol Migraine Pain Relief is contraindicated in patients with severe hepatic or severe renal impairment and failure (e.g. GFR <30mL/min/1.73m2) (see section 4.3), and should be used with caution in patients with mild to moderate hepatic or mild to moderate renal impairment (GFR >30mL/min/1.732) (see section 4.4).

4.3. Contraindications

• Hypersensitivity to acetylsalicylic acid, paracetamol, caffeine or to any of the excipients listed in section 6.1. Patients in whom attacks of asthma, bronchospasm, angioedema, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory drugs such as diclofenac or ibuprofen.

• Active gastric or intestinal ulcer, gastrointestinal bleeding or perforation and in patients with a history of peptic ulceration.

• Haemophilia or other haemorrhagic disorders

• Severe hepatic failure or severe renal impairment or failure (GFR <30mL/min/1.73m2)

• Severe cardiac failure

• Intake of more than 15 mg methotrexate per week (see section 4.5)

• Last trimester of pregnancy (see section 4.6)

4.4. Special warnings and precautions for use

General:

• Panmigrol Migraine Pain Relief should not be taken together with other products containing acetylsalicylic acid or paracetamol.

• As with other acute migraine therapies, before treating a suspected migraine in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions.

• Patients who experience vomiting with > 20% of their migraine attacks or who require bedrest with >50% of their migraine attacks should not use Panmigrol Migraine Pain Relief.

• If the patient gets no migraine relief from the first 2-tablet dose of Panmigrol Migraine Pain Relief, the patient should seek the advice of a physician.

• Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have chronic headaches (15 days or more per month) with concurrent overuse of headache medications for more than 3 months. Therefore, this product should not be used on more than 10 days per month for more than 3 months.

• Caution should be exercised in patients at risk of being dehydrated (e.g. by sickness, diarrhoea, or before or after major surgery).

• Panmigrol Migraine Pain Relief may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Due to the presence of acetylsalicylic acid:

• The concomitant use of acetylsalicylic acid with other systemic NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive undesirable effects (see section 4.5).

• Panmigrol Migraine Pain Relief should be used with caution in patients suffering from gout, impaired renal or hepatic function, dehydration, uncontrolled hypertension, and diabetes mellitus.

• Acetylsalicylic acid in low doses reduces uric acid excretion. Due to this fact, patients who tend to have reduced uric acid excretion may experience gout attacks.

• Acetylsalicylic acid is known to cause sodium and water retention which may exacerbate hypertension, congestive heart failure and renal impairment.

• Panmigrol Migraine Pain Relief should be used with caution in patients suffering from severe glucose-6- phosphate dehydrogenase (G6PD) deficiency, as acetylsalicylic acid may induce hemolysis or hemolytic anemia. Factors that may increase the risk of hemolysis are e.g. high dosage, fever or acute infections.

• Panmigrol Migraine Pain Relief may lead to an increased bleeding tendency during and after surgical operations (including minor surgeries, e.g. dental extractions) because of the inhibitory effect on platelet aggregation of acetylsalicylic acid which persists for about 4 to 8 days after administration.

• Acetylsalicylic acid decreases platelet adhesiveness and increases bleeding time. Hematological and hemorrhagic effects can occur and may be severe. Patients should report any unusual bleeding symptoms to their physician.

• Panmigrol Migraine Pain Relief should not be taken together with anticoagulant or other medicines that inhibit platelet aggregation without a doctor's supervision (see section 4.5). Patients with defects of haemostasis should be carefully monitored. Caution should be exercised in case of metrorrhagia or menorrhagia.

• Panmigrol Migraine Pain Relief must be withdrawn immediately if gastrointestinal (GI) bleeding or ulceration occurs in patients receiving this medicinal product. GI bleeding, ulceration or perforation, which can be fatal, have been reported with all NSAIDs and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. The risk of GI bleeding could be enhanced by alcohol, corticosteroids and NSAIDs (see section 4.5).

• Panmigrol Migraine Pain Relief may precipitate bronchospasm and induce asthma exacerbations (so-called intolerance to analgesics / analgesics-asthma) or other hypersensitivity reactions. Risk factors are present bronchial asthma, seasonal allergic rhinitis, nasal polyps, chronic obstructive pulmonary disease or chronic infection of the respiratory tract (especially if linked to allergic rhinitis-like symptoms). This applies also for patients showing allergic reactions (e.g. cutaneous reactions, itching, urticaria) to other substances. Special precaution is recommended in such patients (readiness for emergency).

• Panmigrol Migraine Pain Relief should not be given to children and adolescents aged under 18 years unless specifically indicated because there is a possible association between acetylsalicylic acid and Reye's syndrome when given to children and adolescents. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal.

• Acetylsalicylic acid can interfere with thyroid function tests due to falsely low concentrations of levothyroxine (T4) or tri-iodothyronine (T3) (see section 4.5).

Due to the presence of paracetamol:

• Paracetamol overdose may cause liver failure which may require liver transplant or lead to death. Underlying liver disease increases the risk of paracetamol- related liver damage.

• The overall benefit-risk should be considered in patients diagnosed with liver or kidney impairment before use.

• Cases of hepatic dysfunction/failure have been reported in patients with depleted glutathione levels, such as those who are severely malnourished, anorexic, have a low body mass index or are chronic heavy users of alcohol or have sepsis.

• In patients with glutathione depleted states, the use of paracetamol may increase the risk of metabolic acidosis.

• The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic medicinal products or medicinal products that induce liver microsomal enzymes (e.g. rifampicin, isoniazide, chloramphenicol, hypnotics and antiepileptics including phenobarbital, phenytoin and carbamazepine).

• Patients should be warned not to take other products containing paracetamol concurrently due to the risk of severe liver damage in case of overdose (see section 4.9).

• Alcoholic beverages should be avoided while taking this medicine because alcohol use in combination with paracetamol may cause liver damage (see section 4.5).

• Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

Due to the presence of caffeine:

• Panmigrol Migraine Pain Relief should be given with care to patients with gout, hyperthyroidism and arrhythmia.

• The patient should limit the use of caffeine containing products when taking Panmigrol Migraine Pain Relief, as excess caffeine may cause nervousness, irritability, sleeplessness and occasionally rapid heart beat.

Information concerning excipients:

• Panmigrol Migraine Pain Relief contains 0.03 mg benzoic acid per tablet. Benzoic acid may increase jaundice in newborn babies (up to 4 weeks old).

4.5. Interaction with other medicinal products and other forms of interaction

Acetylsalicylic acid, paracetamol and caffeine combination medicines should not be used together with other non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid and cylcooxygenase-2 specific inhibitors as these may increase the risk of adverse effects.

Medicinal product interactions with other substances that might be caused by each individual ingredient are well-known and there is no indication that those might change through combined use. There are no safety-relevant interactions between acetylsalicylic acid and paracetamol.

Table 4-1 Acetylsalicylic acid (ASA)

Combination of Acetylsalicylic acid with:

Possible outcome:

Other Non-Steroidal Anti- Inflammatory Drugs (NSAIDs)

There is an increased risk of GI ulcers and haemorrhages due to synergic effects. If concurrent use is necessary, where appropriate, the use of gastroprotection may be considered for prophylaxis of NSAID-induced GI damage. Thus, concomitant use is not recommended (see section 4.4).

Corticosteroids

There is an increased risk of GI ulceration or bleeding due to synergic effects. It may be advisable to consider the use of gastroprotection in patients taking ASA and corticosteroids, especially if they are elderly. Thus, concomitant use is not recommended (see section 4.4).

Oral anticoagulants (e.g. coumarin derivatives)

ASA can increase the anticoagulant effect. Clinical and laboratory monitoring of the bleeding time and prothrombin time should be performed. Concomitant use is therefore not recommended (see section 4.4).

Thrombolytics

There is an increased risk of bleeding. Particularly, treatment with ASA should not be initiated within the first 24 hours after treatment with alteplase in acute stroke patients. Concomitant use is therefore not recommended (see section 4.4).

Heparin & Platelet aggregation inhibitors (ticlopidine, clopidogrel, cilostazol)

There is an increased risk of bleeding. Clinical and laboratory monitoring of the bleeding time should be performed. Concomitant use is therefore not recommended (see section 4.4).

Selective Serotonin Reuptake Inhibitors (SSRIs)

They could affect coagulation or platelet function when concomitantly taken with ASA, leading to increased occurrence of bleeding in general, and in particular GI bleeding. Therefore, concomitant use should be avoided.

Phenytoin

ASA increases its serum levels; serum phenytoin should be well monitored.

Valproate

ASA inhibits its metabolism and hence could increase its toxicity; valproate levels should be well monitored.

Aldosterone antagonists (spironolactone, canrenoate)

ASA may reduce their activity due to inhibition of urinary sodium excretion; blood pressure should be well monitored.

Loop diuretics (e.g. furosemide)

ASA may reduce their activity due to competition and inhibition of urinary prostaglandins. NSAIDs can cause acute kidney failure, especially in dehydrated patients. If a diuretic is administered simultaneously with ASA, it is necessary to ensure adequate hydration of the patient and to monitor the kidney function and blood pressure, particularly when starting diuretic treatment.

Antihypertensives (ACE- inhibitors, angiotensin II receptor antagonists, calcium-channel blockers)

ASA may reduce their activity due to competition and inhibition of urinary prostaglandins. This combination could lead to acute kidney failure in elderly or dehydrated patients. It is recommended that blood pressure and renal function should be well monitored when starting treatment and the patient should be regularly hydrated. In case of association with verapamil the bleeding time should be also monitored.

Uricosurics (e.g. probenecid, sulfinpyrazone)

ASA may reduce their activity due to inhibition of tubular resorption, leading to high plasma levels of ASA.

Methotrexate

≤ 15 mg/week

ASA, like all NSAIDs, reduces the tubular secretion of methotrexate, increasing its plasma concentrations and thereby also its toxicity. The concomitant use of NSAIDs is therefore not recommended in patients treated with high doses of methotrexate (see section 4.3). The risk of interactions between methotrexate and NSAIDs must also be considered for patients who take low doses of methotrexate, especially those with altered kidney function. If combined treatment is necessary, the complete blood count, liver and renal functions should be monitored, especially during the first days of treatment.

Sulphonylureas and insulin

ASA increases their hypoglycaemic effect, thus some downward readjustment of the dosage of the antidiabetic may be appropriate if large doses of salicylates are used. Increased blood glucose controls are recommended.

Alcohol

There is an increased risk of GI bleeding; this combination should be avoided.

Table 4-2 Paracetamol

Combination of paracetamol with:

Possible outcome:

Liver enzyme inducers or potentially hepatotoxic substances (eg., alcohol, rifampicin, isoniazide, hypnotics and antiepileptics including phenobarbital, phenytoin and carbamazepine)

Increased toxicity of paracetamol that could lead to liver damage even with otherwise harmless doses of paracetamol; therefore, liver function should be monitored (see section 4.4). Concomitant use is not recommended.

Chloramphenicol

Paracetamol may increase the risk of elevated plasma concentrations of chloramphenicol. Concomitant use is not recommended.

Zidovudine

Paracetamol could increase the tendency to develop neutropenia; therefore, the hematological blood monitoring should be performed. Concomitant use is not recommended unless monitored by a doctor.

Probenecid

It reduces paracetamol clearance, thus paracetamol doses should be decreased when combined with these agents. Concomitant use is not recommended.

Oral anticoagulants

The repeated use of paracetamol for more than one week increases anticoagulant effects. Sporadic doses of paracetamol do not have a significant effect.

Propantheline or other agents that lead to slowing of gastric emptying

These agents delay paracetamol absorption; rapid pain relief may be delayed and reduced.

Metoclopramide or other agents that lead to acceleration of gastric emptying

These active substances accelerate the paracetamol absorption with increase of the effectiveness and onset of analgesia.

Cholestyramin

It reduces paracetamol absorption; therefore cholestyramin should not be given within 1 hour of paracetamol if maximal analgesia is to be achieved.

Flucloxacillin

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Table 4-3 Caffeine

Combination of caffeine with:

Possible outcome:

Hypnotic agents (eg., benzodiazepines, barbiturates, antihistamines, etc)

Concomitant use can reduce the hypnotic effect, or antagonize the anticonvulsive effects of barbiturates. Concomitant use is therefore not recommended. If needed, the combination may possibly be more useful in the morning.

Lithium

Caffeine withdrawal increases serum lithium since renal clearance of lithium can be increased by caffeine, therefore when caffeine is withdrawn, it may be necessary to reduce the dose of lithium. Concomitant use is therefore not recommended.

Disulfiram

Alcoholic patients who are recovering using treatment with disulfiram must be warned to avoid the use of caffeine in order to avoid the risk of alcohol abstinence syndrome worsening due to caffeine-induced cardiovascular and cerebral excitation.

Substances of the ephedrine type

Their combination could have an increased dependency potential. Concomitant use is therefore not recommended.

Sympathomimetics or levothyroxine

Their combination could have an enhanced tachycardic effect due to synergic effects. Concomitant use is therefore not recommended.

Theophylline

Concomitant use could reduce the excretion of theophylline.

Antibacterials of the quinolone type (ciprofloxacin, enoxacin, and pipemidic acid), terbinafine, cimetidine, fluvoxamine and oral contraceptives

Increased caffeine half-life due to inhibition of the hepatic cytochrome P - 450 pathway; therefore, patients with hepatic disorders, cardiac arrhythmias or latent epilepsy should avoid taking caffeine.

Nicotine, phenytoin and phenylpropanolamine

They decrease the elimination half-life of caffeine.

Clozapine

Caffeine increases the serum levels of clozapine due to the probable interaction through both pharmacokinetic and pharmacodynamic mechanisms. Clozapine serum levels should be monitored. Concomitant use is therefore not recommended.

Interaction with laboratory testing

• High doses of ASA can affect the results of several clinical-chemical laboratory tests.

• Paracetamol intake can affect the results of uric acid when using the phosphotungstic acid method and for glycaemia when using the glucose oxidase/peroxidase method.

• Caffeine can inverse the effects of dipyridamole and adenosine on myocardial blood flow, thereby interfering with the results of myocardial imaging tests. It is recommended that the ingestion of caffeine be suspended at least 24 hours prior to the test.

4.6. Fertility, pregnancy and lactation

Pregnancy

Not recommended for use during pregnancy. This medicine is contraindicated during the third trimester of pregnancy (see section 4.3).

There are no adequate data available from the use of Panmigrol Migraine Pain Relief in pregnant women. Animal studies have not been performed with acetylsalicylic acid, paracetamol and caffeine in combination (see section 5.3).

Acetylsalicylic acid

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, acetylsalicylic acid should not be given unless clearly necessary. If acetylsalicylic acid is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may have the following effects:

On the foetus:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

On the mother and the neonate:

• at the end of pregnancy, possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;

• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Paracetamol

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy, however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Caffeine

There is evidence that the prolonged intake of high amounts of caffeine may lead to spontaneous abortion or premature birth in pregnant women. Non-clinical studies have shown reproductive toxicity at very high doses.

Breast-feeding

Salicylate, paracetamol and caffeine are excreted into breast milk. Due to the content of caffeine, the behaviour of the suckling child may be influenced (excitement, poor sleeping pattern). Due to the salicylate, there may also be a potential for adverse effects on platelet function in the infant (could cause slight bleeding), though none have been reported. Also, there are concerns with the use of ASA in case of potential development of Reye's Syndrome in infants. Therefore, Panmigrol Migraine Pain Relief is not recommended during breastfeeding.

Fertility

Acetylsalicylic acid

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

4.7. Effects on ability to drive and use machines

No studies on the effects of the ability to drive and use machines have been performed. If you notice undesirable effects such as dizziness or drowsiness, you should not drive or use machines. Tell your doctor as soon as possible.

4.8. Undesirable effects

Many of the following adverse reactions are clearly dose-dependent and variable from one person to another.

Table 4-4 provides a listing of adverse reactions from 16 single-dose clinical studies on the efficacy and safety of Panmigrol Migraine Pain Relief in the treatment of migraine, headache or dental pain associated with tooth extraction, involving 4809 Panmigrol Migraine Pain Relief-treated subjects, and from post- marketing spontaneous reports. The adverse reactions included in the table were those regarded as at least possibly related to the administration of Panmigrol Migraine Pain Relief and are listed in descending order of frequency within MedDRA System Organ Classification.

For adverse reactions from the spontaneous reporting system, the frequencies cannot be reliably determined and therefore, is not known.

Adverse reactions are listed below by system organ class and frequency, using the following convention: 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), including isolated reports and not known (cannot be estimated from the available data).

Table 4-4 Adverse reactions reported from clinical studies and from post- marketing spontaneous reports

System Organ Class

Frequency

Preferred Term

Infections and infestations

Rare

Pharyngitis

Blood and lymphatic system disorders

Not known

Prolonged bleeding time, thrombocytopenia, ecchymosis

Immune system disorders

Not Known

Hypersensitivity*, anaphylactic reaction, Stevens Johnson syndrome, toxic epidermal necroysis

Metabolism and nutrition disorders

Rare

Not known

Decreased appetite

Sodium and fluid retention, High anion gap metabolic acidosis**

Psychiatric disorders

Common

Nervousness

Uncommon

Insomnia

Rare

Anxiety, euphoric mood, tension

Not Known

Restlessness

Nervous system disorders

Common

Dizziness

Uncommon

Tremor, paraesthesia, headache

Rare

Dysgeusia, disturbance in attention, amnesia, coordination abnormal, hyperaesthesia, sinus headache

Not Known

Migraine, somnolence

Eye disorders

Rare

Eye pain, visual disturbance

Ear and labyrinth disorders

Uncommon

Tinnitus

Not known

Temporary hearing loss.

Cardiac disorders

Uncommon

Arrhythmia

Not Known

Palpitations

Vascular disorders

Rare

Flushing, peripheral vascular disorder

Not Known

Hypotension

Respiratory, thoracic and mediastinal disorders

Rare

Epistaxis, hypoventilation, rhinorrhoea

Not known

Bronchospasm

Not Known

Dyspnoea, asthma

Gastrointestinal disorders

Common

Nausea, abdominal discomfort

Uncommon

Dry mouth, diarrhoea, vomiting

Rare

Eructation, flatulence, dysphagia, paraesthesia oral, salivary hypersecretion

Not Known

Abdominal pain upper, dyspepsia, abdominal pain, GI haemorrhage (including upper GI haemorrhage, gastric haemorrhage, gastric ulcer haemorrhage, duodenal ulcer haemorrhage, rectal haemorrhage), GI ulcer (including gastric ulcer, duodenal ulcer, large intestinal ulcer, peptic ulcer), gastritis

Hepatobiliary disorders

Not Known

Hepatic failure, hepatic enzyme increased, Reye's syndrome (see section 4.3)

Skin and subcutaneous tissue disorders

Rare

Hyperhidrosis, pruritus, urticaria

Not Known

Erythema, rash, angioedema, erythema multiforme

Musculoskeletal and connective tissue disorders

Rare

Musculoskeletal stiffness, neck pain, back pain, muscle spasms

Renal and urinary disorders

Not known

Renal dysfunction, increased blood uric acid levels

General disorders and administration site conditions

Uncommon

Fatigue, feeling jittery

Rare

Asthenia, chest discomfort

Not Known

Malaise, feeling abnormal

*including rhinitis

**Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

Very rare cases of serious skin reactions have been reported.

There is no information available to suggest that the extent and type of adverse events of the individual substances is enhanced or the spectrum broadened when the fixed combination is used as instructed.

Increase of the risk of bleeding can persist for 4-8 days after the intake of acetylsalicylic acid. Very rarely severe bleeding (e.g. intracerebral bleeding) especially in patients with untreated hypertension and / or concomitant treatment with anticoagulants. In single cases these can be life threatening.

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

Linked to Acetylsalicylic acid:

Symptoms of mild salicylate intoxication include dizziness, tinnitus, deafness, sweating, warm extremities with bounding pulses, nausea and vomiting, dehydration, headache and confusion. These may occur at plasma concentrations of 150 to 300 micrograms/ml. These symptoms can be controlled by reducing the dose, or interrupting the treatment.

More serious intoxication occurs at concentrations above 300 micrograms/ml. The symptoms of severe overdose include hyperventilation, fever, restlessness, ketosis, respiratory alkalosis, and metabolic acidosis. Depression of the CNS may lead to coma. Cardiovascular collapse and respiratory failure may also occur.

Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopenia, 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.

Treatment of severe overdose

The patient must be transferred to hospital and the Poison Control Center contacted immediately.

When the patient is suspected of ingesting more than 120 mg/kg salicylate within the last hour, repeated doses of activated charcoal are to be given orally.

Plasma concentrations should be measured in patients having ingested more than 120 mg/kg salicylate, although the severity of the poisoning cannot be determined from these alone. Clinical and biochemical features must equally be taken into account.

In plasma concentrations exceeding 500 micrograms/ml (350 micrograms/ml in children under 5 years of age) the intravenous administration of sodium bicarbonate is effective in removing salicylate from the plasma. Forced diuresis should not be used alone since it does not enhance salicylate excretion and may cause pulmonary oedema.

Heamodialysis or haemoperfusion are the methods of choice in cases where the plasma salicylate concentration is more than 700 micrograms/ml, or lower in children and elderly people, or if there is a severe metabolic acidosis.

Linked to Paracetamol:

Overdose (>10 g in total in the adult or >150 mg/kg in one intake) can provoke a hepatic cytolysis which can lead to complete and irreversible necrosis (hepatic failure, metabolic acidosis, renal failure) and eventually to coma and possibly death or may require liver transplant. Less often renal tubular necrosis may develop.

Early signs of overdose (very commonly nausea, vomiting, anorexia, pallor, lethargy and sweating) generally settle within first 24 hours.

Abdominal pain may be the first indication of liver damage, which is not usually apparent for the first 24 to 48 hours, and may be delayed for up to 4 to 6 days after ingestion. Liver damage is generally at a maximum 72 to 96 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Patients are considered at high risk when receiving enzyme-inducing medicinal products, such as carbamazepine, phenytoin, phenobarbital, rifampicin, and St John's wort, or with a history of alcohol abuse, or suffering from malnutrition.

Treatment of overdose:

Immediate medical management is required in the event of overdose, even if symptoms of overdose are not present.

If overdose is confirmed or suspected, seek immediate advice from your Poison Centre and refer patient to nearest Emergency Medical Centre for management and expert treatment. This should happen even in patients without symptoms or signs of overdose due to the risk of delayed liver damage.

When the patient is suspected of ingesting more than 150 mg/kg paracetamol within the last hour, repeated doses of activated charcoal are to be given orally. However, if acetylcysteine or methionine is to be given by mouth the charcoal is best cleared from the stomach to prevent it reducing the absorption of the antidote.

Antidotes

N-acetylcysteine should be administered intravenously or orally as soon as possible after ingestion. It is most effective during the first 8 hours after taking the overdose. The effect of the antidote then diminishes progressively after that. Nevertheless it has been shown that treatment up to and beyond 24 hours after ingestion remains beneficial.

Methionine is most effective within the first 10 hours after ingestion of paracetamol overdose. Hepatic damage is more frequent and severe if treatment with methionine if started more than 10 hours after ingestion.

Oral absorption might be reduced by vomiting or activated charcoal.

Linked to Caffeine:

Common symptoms include epigastric pain, vomiting, anxiety, nervousness, restlessness, insomnia, excitement, muscle twitching, confusion, tremors and convulsions. For high intake of caffeine, hyperglycemia could also appear. Cardiac Symptoms include tachycardia and cardiac arrhythmia. The symptoms are controlled by reducing or stopping caffeine intake.

For clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.