EXCEDRIN

PATIENT LEAFLET IN ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) – 1986

This medicine is dispensed without a doctor's prescription

Excedrin caplets, 250 mg/250 mg/65 mg

Active ingredients and their amounts:

Each caplet contains:

Acetylsalicylic acid

250 mg

Paracetamol

250 mg

Caffeine

65 mg

For a list of inactive ingredients and allergens - see section 6.

Read the entire leaflet carefully before using the medicine.

This leaflet contains

concise information about the medicine. If you have any other questions, refer to the

doctor or the pharmacist.

Take the preparation according to the instructions in section 3 - How should you use

the medicine. Consult the pharmacist if you need more information. Refer to the

doctor if signs of the ailment (symptoms) worsen or do not improve after 5 days of

pain treatment or after 3 days of treatment of pain accompanied by fever (see

section 3 - How should you use the medicine).

1. What is the medicine intended for?

The medicine is intended for temporary relief of headaches, mild to moderate pain

related to migraines, pain of menstrual discomfort and pain accompanied by fever.

Therapeutic class:

Acetylsalicylic acid -

non-steroidal anti-inflammatory drug (NSAIDs)

Paracetamol -

analgesic and antipyretic

Caffeine -

xanthine alkaloid, central nervous system stimulant

2. Before using the medicine

Do not use this medicine if:

You are sensitive

(allergic)

to the active ingredients

to any of the

additional components the medicine contains

(see section 6).

Symptoms of an allergic reaction

may include: Asthma, wheezing or

shortness of breath, skin rash or hives, swelling of the face or tongue,

runny nose. If you are unsure, ask your doctor or pharmacist.

You had an allergic reaction in the past

to other

medicines used to

treat pain, inflammation or fever

, such as diclofenac or ibuprofen.

You have

a stomach or intestinal ulcer

, or if you have a

history of

peptic ulceration

You have

observed blood in the stool or black stool

(symptoms of

bleeding or perforations in the digestive tract).

You are a

hemophiliac or suffering from other blood disorders.

You have

severe problems in the heart, liver and kidneys.

You are taking

more than 15 mg of methotrexate per week

(see the

Drug-drug interactions section

You are

in the last three months of pregnancy

(see the “Pregnancy,

breastfeeding and fertility” section).

Special warnings regarding the use of the medicine

Before taking Excedrin, inform the doctor if:

You have not been diagnosed with migraines in the past, since potentially

severe conditions that are related to the brain or the nervous system should

be ruled out before treatment.

You have a

migraine

acute

that it

necessitates bedrest

, or if you have a

headache that is different from your usual migraines, or if

the migraine

headaches are accompanied by vomiting

You started to have

headaches after or due to a head injury, exertion,

cough or bending over

You have chronic headaches (fifteen days or more in one month for more

than three months), or if you have experienced your first headache after the

age of 50.

You are suffering from a hereditary condition called

G6PD (Glucose-6-

Phosphate Dehydrogenase) deficiency

, which affects the red blood cells

and may cause anemia, jaundice or spleen enlargement upon exposure to

certain types of food and to medicines such as certain anti-inflammatory

medicines (e.g. acetylsalicylic acid (aspirin)), or cause other illnesses.

You had problems

in the digestive system

such as gastric ulcer, bleeding or

black stool in the past. You had abdominal discomfort or heartburn after

taking analgesics or anti-inflammatory medicines.

You are suffering from

bleeding disorders or abnormal vaginal bleeding

that differs from your menstrual period (e.g., an unusually heavy and

prolonged menstrual period).

You have recently undergone a

surgical operation

(including minor ones

such as dental surgery), or will undergo one within the next seven days.

You have

adult asthma, hay fever (allergic rhinitis), nasal polyps, chronic

respiratory disease or you are developing allergic symptoms

(such as

skin reactions, itching, urticaria)

You have

gout, diabetes, hyperthyroidism (overactive thyroid),

arrhythmias, uncontrolled hypertension, impaired kidney or liver

function

You are

addicted to alcohol

(see the “Use of the medicine and food”

section).

You are

taking other medicines that contain acetylsalicylic acid (aspirin)

or paracetamol,

or other medicines, since certain medicines may interfere

with Excedrin and cause side effects (see the “Drug-drug interactions”

section)

You are at

risk of being dehydrated

(e.g. due to vomiting, diarrhea, or

before or after a major surgery).

You are less than 18 years old.

There is a possible association between

acetylsalicylic acid (aspirin) and Reye’s Syndrome when the medicine is given

to children and adolescents. Reye’s Syndrome is a rare syndrome which

affects the brain and the liver and can be fatal. For that reason, Excedrin

should not be used in adolescents and children under 18 years old without an

explicit instruction from the doctor.

Additional warnings:

As with any type of headache analgesics, taking Excedrin too often (i.e. more than

ten days per month for this medicine) with concurrent chronic headaches (fifteen

days or more per month), for more than three months, could worsen your headache

or migraine.

If you think this might be the case, consult with your doctor. You may have to stop

taking Excedrin to resolve this problem.

Excedrin may reduce the symptoms of infection (e.g. headache, high temperature)

and may therefore make it more difficult to detect. If you are feeling unwell and need

to see a doctor, remember to inform him or her that you are taking Excedrin.

Children and adolescents

Excedrin is not intended for children and adolescents under the age of 12.

Tests and follow-up

Excedrin may affect the results of laboratory tests. If you have been asked to have

blood, urine or other lab tests, remember to tell that you are taking Excedrin.

Drug-drug interactions:

If you are taking or have recently taken other medicines, including non-

prescription medicines and food supplements, tell the doctor or the

pharmacist.

Especially if you are taking:

Any other preparation that contains paracetamol, acetylsalicylic acid

(aspirin) or any other analgesic/antipyretic.

Medicines used to prevent blood clotting

such as oral anticoagulants (e.g.

warfarin), heparin, thrombolytics (e.g. streptokinase) or other anti-platelets

(ticlopidine, clopidogrel, cilostazol).

Corticosteroids

(used for relieving inflammation).

Barbiturates and benzodiazepines

(for treatment of anxiety and insomnia).

Lithium, SSRIs (Selective Serotonin Reuptake Inhibitors) or fluvoxamine

(for treatment of depression).

Sulfonylurea and insulin

(for treatment of diabetes).

Methotrexate

(for treatment of certain types of cancer, arthritis or psoriasis).

Certain medicines for treating infections

(e.g. rifampicin, isoniazid,

chloramphenicol, ciprofloxacin or pipemidic acid).

Levothyroxine

(for treatment of hypothyroidism (underactive thyroid)).

Metoclopramide

(for treatment of nausea and vomiting).

Medicines for treatment of epilepsy.

Medicines for treatment of hypertension and heart failure.

Diuretics

(for increasing urine production and reducing excessive fluids).

Medicines for treatment of gout.

Oral contraceptives.

Zidovudine

(for treatment of human immunodeficiency virus (HIV)).

Medicines for treatment of slow gastric emptying,

such as propantheline.

Clozapine

(for treatment of schizophrenia).

Sympathomimetic agents

(for raising blood pressure or treating nasal

congestion).

Anti-allergy medicines

(for treatment or relief of allergies).

Theophylline

(for treatment of asthma).

Terbinafine

(for treatment of fungal infections).

Cimetidine

(for treatment of heartburn and peptic ulcers).

Disulfiram

(for treatment of alcohol dependence).

Nicotine

(for smoking cessation).

Cholestyramine

(for treatment of high cholesterol levels).

Use of the medicine and food:

The recommended dose of this medicine contains an amount of caffeine similar to

that in a cup of coffee. While using this medicine, limit your intake of caffeine-

containing medicines, foods and beverages, because too much caffeine may cause

nervousness, irritability, sleeplessness, and occasionally, rapid heartbeat.

Use of the medicine and alcohol consumption:

You should refrain from alcohol consumption during treatment with this medicine. If

you are consuming three or more alcoholic beverages a day, ask your doctor

whether you should take this medicine or other medicines for relieving pain/lowering

fever. Paracetamol and acetylsalicylic acid (aspirin) may damage the liver and cause

stomach bleeding.

Pregnancy, breastfeeding and fertility:

If you are pregnant, think you might be pregnant or are planning to become

pregnant,

inform your doctor and do not take Excedrin

It is especially important not to take Excedrin during the last three months of the

pregnancy, since it may harm the fetus or cause problems during labor.

Excedrin is not recommended for breastfeeding mothers.

Consult with your doctor or pharmacist before taking any medicine.

Excedrin belongs to a group of medicines (NSAIDs) which may impair women’s

fertility. This effect is reversible when the medicine is stopped.

Driving and operating machinery:

Taking Excedrin has no known effect on your ability to drive and operate machinery.

If you notice side effects such as dizziness or drowsiness, you should avoid driving

and operating machinery. Tell your doctor as soon as possible.

3. How should you use the medicine?

Check with the doctor or pharmacist if you are uncertain about the dosage and how

to use the medicine.

The generally accepted dosage is:

For treatment of migraine-related headaches:

Adults: Two caplets. If the medicine was taken for a migraine with no improvement,

or if it became worse after one dose, consult a doctor.

Children under 18: Consult a doctor.

Do not take the medicine for more than 48 hours for treatment of a migraine.

For headaches, pain of menstrual discomfort and pain accompanied by fever:

Adults and children over the age of 12 years: 2 caplets every 6 hours.

Pain relief may be felt within 15 minutes of taking the dose.

Do not take more than 8 caplets in 24 hours.

Do not exceed the recommended dose.

Do not use this medicine for more than 5 days for pain or 3 days for pain with fever

without consulting the doctor.

Elderly:

There are no special dosage recommendations. If you have low body weight, you

should seek the advice of a doctor or a pharmacist.

The medicine should be swallowed whole with a full glass of water.

Halving/crushing/chewing:

The caplet should not be halved or crushed.

No information regarding halving/crushing/chewing is available.

Do not lie down for 15-30 minutes after taking the medicine.

Excedrin caplets contain acetylsalicylic acid (aspirin), paracetamol and caffeine. Do

not take more than the recommended dosage and do not take other medicines that

may contain these ingredients or other ingredients for treatment of pain,

inflammation or high fever (non-steroidal anti-inflammatory drugs) while using

Excedrin.

If you took an overdose or if a child accidentally swallowed this medicine, go to the

doctor or the emergency room of a hospital immediately and take the package of the

medicine with you.

Immediate medical treatment is critical, due to the possible risk of irreversible

damage to the liver on account of the paracetamol. Do not wait for the appearance of

symptoms, since in the beginning the overdose may not cause noticeable symptoms.

If symptoms of overdose do appear, they may be:

acetylsalicylic acid (aspirin):

Dizziness, ringing in the ears, deafness,

sweating, hyperventilation, high fever, nausea, vomiting, headache, confusion

or restlessness, circulatory collapse or respiratory failure.

paracetamol

: Initial symptoms that may appear are nausea, vomiting,

loss of appetite, pallor, drowsiness, sweating and later abdominal pain.

caffeine:

Anxiety, nervousness, restlessness, insomnia, excitement,

muscle cramps, confusion, convulsions, hyperglycemia (high blood sugar),

tachycardia (rapid heartbeat) or cardiac arrhythmia.

Even if these symptoms do not appear or if they resolve, it is vital to seek

medical help immediately.

If you forgot to take the medicine

Take the medicine as soon as you remember, but do not take a double dose to

compensate for a forgotten dose.

Do not take more than 8 caplets in 24 hours.

Do not take medicines in the dark! Check the label and the dose every time

you take a medicine. Wear glasses if you need them.

If you have any other questions regarding the use of the medicine, consult the

doctor or the pharmacist.

4. Side effects

As with any medicine, using Excedrin may cause side effects in some users. Do not

be alarmed when reading the list of side effects. You may not experience any of

them.

Discontinue treatment and contact a doctor immediately if you experience one

or more of the following severe side effects:

An allergic reaction with swelling of the face, lips, mouth, tongue or throat.

This may cause difficulty in swallowing, wheezing, breathing difficulties, and

feeling of tightness in the chest (signs of asthma). You may also have a rash

or itching, or you may faint.

A skin rash (including hives, itching), skin redness, blisters in the lips, eyes or

mouth, skin peeling, sores, mouth ulcers.

Stomach or intestinal bleeding, stomach or intestinal ulcer, which may be

accompanied by acute abdominal pain, bloody or black stool or bloody vomit.

As with all analgesics and antipyretics, this can happen at any time during the

treatment, without prior history, and may be fatal. This side effect is especially

severe in the elderly.

Yellowing of the skin or eyes (signs of liver failure).

Dizziness (signs of low blood pressure).

Irregular heartbeat.

Additional side effects

The following side effects have been reported in 16 clinical trials done with Excedrin

on more than 4800 patients.

Tell your doctor if you notice any of the following side effects:

Common side effects - side effects that occur in up to 1 out of 10 users:

Nervousness, dizziness

Nausea, abdominal discomfort

Uncommon side effects - side effects that occur in up to 1 out of 100 users:

Insomnia, tremor, numbness, headache

Ringing in the ears

Dry mouth, diarrhea, vomiting

Tiredness, feeling of nervousness

Increase in heart rate

Rare side effects – side effects that occur in up to 1 out of 1,000 users:

Sore throat, difficulty swallowing, numbness or tingling around the mouth,

excessive saliva

Decreased appetite, altered taste

Anxiety, euphoric mood, stress

Attention disorders, memory loss, changes in coordination

Pain sensation in the cheeks and forehead

Eye pain, vision disturbances

Hot flashes, problems in peripheral blood vessels (such as in the arms or

legs)

Nose bleeds, slow and shallow breathing, runny nose

Burping, flatulence

Excessive sweating, itching, itchy rash, increased skin sensitivity

Muscle, bone or joint rigidity, neck pain, back pain, muscle cramps

Weakness, chest discomfort

Side effects with unknown frequency (effects whose frequency has not yet been

determined):

The following side effects have also been reported since the beginning of marketing

of Excedrin. In general, the frequency during post-marketing surveillance cannot be

determined precisely, thus it is indicated as “unknown”:

Restlessness, general bad or abnormal feeling

Somnolence, migraine

Skin reddening, rash. Very rare cases of severe skin reactions have been

reported.

Palpitations, shortness of breath, sudden breathing difficulties, and feeling of

tightness in the chest with wheezing or cough (asthma)

Abdominal pain, abdominal discomfort after meals

Liver enzymes elevation

If a side effect occurs, if one of the side effects worsens, or if you suffer from a

side effect not mentioned in this leaflet, consult your doctor.

Side effects may be reported to the Ministry of Health by clicking on the link "report

side effects due to medicinal treatment" found on the Ministry of Health website

homepage (www.health.gov.il), which will direct you to the online form for reporting

side effects, or by clicking on the following link:

https://sideeffects.health.gov.il/

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine must be kept in a

closed place out of the reach and sight of children and/or infants to avoid

poisoning. Do not induce vomiting without an explicit instruction from the

doctor.

Do not use the medicine after the expiry date (exp. date) appearing on the

package. The expiry date refers to the last day of that month.

Store at a temperature lower than 25°C.

6. Additional information

In addition to the active ingredients, the medicine also contains:

Cellulose microcrystalline, Hydroxypropyl cellulose low substitution,

Hypermellose, Stearic acid, Titanium dioxide, propylene glycol, Carnauba

wax, Benzoic acid

What does the medicine look like and what are the contents of the package

A white, oblong caplet, with the letter E embossed on one side, without a

score line.

Caplets are packed in blisters, in packs of 8, 10, 16, 20, 30, 32 or 50 caplets.

Not all package sizes may be marketed.

License holder and the address: GSK Consumer Healthcare Israel Ltd., 25

Basel st., Petah Tikva.

Name and address of the manufacturer: GSK Consumer Health SA, Nyon,

Switzerland.

This leaflet was reviewed and approved by the Ministry of Health in February

2014 and has been updated in accordance with the Ministry of Health

instructions in March 2020.

Registration number of the medicine in the National Drug Registry of the

Ministry of Health: 114-82-31782

Exced RLPT v2 402401

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Excedrin

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One caplets contains 250 mg acetylsalicylic acid, 250 mg paracetamol and 65 mg caffeine.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Caplets.

White, oblong-shaped, caplet with the letter “E” debossed on one face.

4 Clinical particulars

4.1 Therapeutic indications

For temporary relief of the pain of headache, mild to moderate pain associated with migraine

headache, pain of menstrual discomfort and pain accompanied by fever.

4.2 Posology and method of administration

Posology

For headache, pain of menstrual discomfort and pain accompanied by fever:

Adults and Adolescents above 12 years: The usual recommended dosage is 2 caplets every

6 hours.

Pain relief may be felt within 15 minutes of administration the dose.

For migraine headache:

Adults- 2 caplets. If Excedrin is taken for migraine headache, and there is no improvement or

there is an exacerbation after the first dose, reconsider the treatment.

Do not use Excedrin for Migraine headache more than 24 hours

Intake should be limited for 8 caplets in 24 hours.

Intake period should be limited for up to 5 days for pain relief and up to 3 days for

pain accompanied by fever.

Drink a full glass of water with each dose.

Do not score or crush the capsule.

Do not lie down for 15-30 minutes after administration the capsule.

Children and adolescents

Excedrin is not indicated for children and adolescents under 12 years old.

Elderly

Based on general medical considerations, caution should be exercised in the elderly, particularly

in elderly patients with low bodyweight.

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, 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 inpatients with

a history of peptic ulceration.

Haemophilia or other haemorrhagic disorders

Severe hepatic or renal failure

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:

Excedrin should not be taken together with 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 Excedrin.

If the patient gets no migraine relief from the first 2-caplet dose of Excedrin, 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. bysickness, diarrhoea,

or before or after major surgery).

Excedrin may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Due to the presence of acetylsalicylic acid:

Excedrin should be used with caution in patients suffering from gout, impaired renal or

hepatic function, dehydration, uncontrolled hypertension, and diabetes mellitus.

Excedrin 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.

Excedrin 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 days

after administration.

Excedrin 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.

Excedrin 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).

Excedrin 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).

Excedrin 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 section4.5).

Due to the presence of paracetamol:

Excedrin should be given with care to patients with impaired renal or hepatic function or

alcohol dependence.

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 with history

of alcohol abuse are at special risk of hepatic damage (see section 4.5).

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). Paracetamol should

be given with caution to patients with alcohol dependence

Due to the presence of caffeine:

Excedrin should be given with care to patients with gout, hyperthyroidism and arrhythmia.

The patient should limit the use of caffeine containing products when taking Excedrin, as

excess caffeine may cause nervousness, irritability, sleeplessness and occasionally rapid

heart beat.

4.5 Interaction with other medicinal products and other forms of interaction

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 wellmonitored.

Aldosterone antagonists

(spironolactone,

canrenoate)

ASA may reduce their activity due to inhibition of urinary sodium excretion;

blood pressure should be wellmonitored.

Loop diuretics (e.g.

furosemide)

ASA may reduce their activity due to competition and inhibition of urinary

prostaglandins. NSAIDs can cause acute kidney failure, especiallyin 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 andthe 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 ofmethotrexate, 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 beconsidered for patients who take low doses of

methotrexate, especially thosewith 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 shouldbe

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.

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.

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data available from the use of Excedrin in pregnant women. Animal

studies have not been performed with acetylsalicylic acid, paracetamol and caffeine in

combination (see section 5.3).

Acetylsalicylic acid

Due to the presence of acetylsalicylic acid in Excedrin, its use is contraindicated in the 3

trimester

of pregnancy (see section 4.3), and caution should be exercised when used in the first 2 terms of

pregnancy.

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

Epidemiological studies indicate that under normal therapeutically conditions paracetamol can be

used during pregnancy. Nevertheless, it should be used only after a careful benefit-risk assessment

has been done.

Caffeine

Pregnant women are advised to limit their intake of caffeine to a minimum as the available data

on the effect of caffeine on the human fetus suggests a potential risk.

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, Excedrin 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.

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.

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 Excedrin in the treatment of migraine, headache or dental pain associated with tooth

extraction, involving 4809 Excedrin-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 Excedrin 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

Immune system disorders

Not Known

Hypersensitivity, anaphylactic reaction, Stevens

Johnson syndrome*, toxic epidermal necroysis*

Metabolism and nutrition

disorders

Rare

Decreased appetite

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

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

Dyspnoea, asthma

Gastrointestinal disorders

Common

Nausea, abdominal discomfort

Uncommon

Dry mouth, diarrhoea, vomiting

Rare

Eructation, flatulence, dysphagia,

paraesthesiaoral, salivaryhypersecretion

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, largeintestinal ulcer, peptic

ulcer)

Hepatobiliary disorders

Not Known

Hepatic failure, hepatic enzymeincreased

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

General disorders and

administration site

conditions

Uncommon

Fatigue, feeling jittery

Rare

Asthenia, chest discomfort

Not Known

Malaise, feeling abnormal

*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. Any suspected

adverse events should be reported to the Ministry of Health according to the National Regulation

by using an online form https://sideeffects.health.gov.il/

4.9 Overdose

Linked to Acetylsalicylic acid:

Symptoms of mild salicylate intoxication include dizziness, tinnitus, deafness, sweating,

nausea and vomiting, 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.

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.

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. 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:

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 anxiety, nervousness, restlessness, insomnia, excitement, muscle

twitching, confusion, 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other analgesics and antipyretics; Salicylic acid and derivatives

ATC code: N02B A51.

Acetylsalicylic acid has analgesic, antipyretic and anti-inflammatory properties, primarily due to

the inhibition of the biosynthesis of prostaglandins and thromboxanes from arachidonic acid by

irreversible acetylation of cyclooxygenase (COX) enzymes.

Paracetamol has analgesic and antipyretic properties, but unlike acetylsalicylic acid does not

inhibit platelet aggregation.

The addition of caffeine augments the antinociceptive effects of acetylsalicylic acid and

paracetamol.

Migraine studies

The efficacy of Excedrin caplets in the treatment of acute migraine attacks was confirmed

in 3 single-dose, double-blind, placebo-controlled studies and in 2 single-dose, double-blind,

placebo and active controlled studies, one versus ibuprofen 400 mg and the other one versus

sumatriptan 50 mg. In these studies, single-dose of Excedrin consisted of 2 tablets (500 mg

acetylsalicylic acid, 500 mg paracetamol, 130 mg caffeine).

In the three placebo-controlled studies, Excedrin APC was superior to placebo in reducing migraine

pain intensity to mild or none 2 hours after dose in the drug–treated patients. It started relieving

migraine symptoms, such as migraine pain, within 30 minutes.

In a placebo and active controlled study, Excedrin APC and ibuprofen (2 tablets of ibuprofen 200

mg) were compared in the treatment of migraine. Excedrin APC was shown to deliver significantly

greater pain relief than ibuprofen starting at 2 hours post dose and to deliver clinically meaningful

pain relief 20 minutes faster.

In another placebo and active controlled pilot study, Excedrin APC was compared with

sumatriptan 50 mg and placebo for the early treatment of migraine. In this study Excedrin APC was

shown to be significantly more effective than sumatriptan 50 mg at reducing migraine pain

intensity throughout the 4-hour treatment period. Sumatriptan 50 mg was shown to be superior

to placebo with respect to this variable, but not to a statistically significant degree.

In a separate placebo and active controlled post-marketing study, Excedrin was not shown to be

non-inferior to sumatriptan 100 mg. However in the acute treatment of migraine, Excedrin

provided pain and symptom relief over 24 hours.

Overall, the efficacy of Excedrin has been demonstrated in the relief of migraine symptoms such as

headache, nausea, sensitivity to light and sound, and functional disability.

Headache studies

The efficacy of Excedrin tablets was studied in 4 independent, multi-center, double-blind,

paracetamol 1000 mg and placebo-controlled crossover studies in the treatment of episodic

tension-type headache. In all of these studies, Excedrin was shown to be consistently superior to

placebo and active comparators (mono-substances) regarding all efficacy measures of pain

intensity and relief throughout the observation period.

Another multi-centre, double-blind, tension-type headache clinical trial compared the onset of

analgesia between Excedrin, placebo and ibuprofen 400 mg. In this study, Excedrin-treated

subjects reported significantly greater pain relief than placebo-treated subjects from 15 minutes

through 4 hours. This finding was evident in both the Pain Relief and Responders endpoints.

5.2 Pharmacokinetic properties

Acetylsalicylic acid

Absorption is generally rapid and complete following oral administration. It is largely hydrolysed to

salicylate in the gastrointestinal tract, liver and blood, and is then further metabolised primarily in

the liver.

Paracetamol