ESPIDIFEN 400 mg ORAL SOLUTION GRANULES, MINT FLAVOR

2. What you need to know before taking Espidifen

Do not take Espidifen:

• If you are allergic to ibuprofen or any of the other components of the medication (listed in section 6). Allergic reactions may include: skin rash with itching, swelling of the face, lips, or tongue, nasal discharge, difficulty breathing, bronchospasm, or asthma.
• If you have a severe liver or kidney disease.
• If you have had a stomach or duodenal ulcer or have suffered a perforation of the digestive tract.
• If you vomit blood.
• If you have black stools or bloody diarrhea.
• If you have an active cerebral hemorrhage or other active bleeding.
• If you have bleeding disorders or blood coagulation disorders, or are taking anticoagulants (medications used to "thin" the blood). If it is necessary to use anticoagulant medications at the same time, your doctor will perform blood coagulation tests.
• If you have severe heart failure.
• If you have severe dehydration caused by vomiting, diarrhea, or insufficient fluid intake.
• If you are in the third trimester of pregnancy.

Warnings and Precautions

Consult your doctor before starting to take Espidifen:

• If you have edema (fluid retention).
• If you have or have had heart disorders or high blood pressure.
• If you have asthma or any other respiratory disorder.
• If you have an infection;

Espidifen may mask the signs of an infection, such as fever and pain. Consequently, Espidifen may delay the appropriate treatment of the infection, which may increase the risk of complications. This has been observed in bacterial pneumonia and bacterial skin infections related to chickenpox. If you take this medication while having an infection and the symptoms of the infection persist or worsen, consult a doctor without delay.

• If you have kidney or liver disease, are over 60 years old, or need to take the medication for a prolonged period (more than 1 to 2 weeks), your doctor may need to perform regular checks. Your doctor will indicate the frequency of these checks.
• If you experience symptoms of dehydration, e.g., severe diarrhea or vomiting, take plenty of fluids and contact your doctor immediately, as ibuprofen may cause kidney failure due to dehydration in this case.
• If you have had or developed an ulcer, bleeding, or perforation in the stomach or duodenum, which may be manifested by severe abdominal pain or persistent abdominal pain and/or black stools, or even without previous warning symptoms.

This risk is higher when using high doses and prolonged treatments, in patients with a history of peptic ulcers, and in elderly patients. In these cases, your doctor will consider the possibility of associating a stomach-protecting medication.

• If you take medications that alter blood coagulation, such as oral anticoagulants, antiplatelet agents of the aspirin type. You should also discuss the use of other medications that may increase the risk of such bleeding, such as corticosteroids and selective serotonin reuptake inhibitor antidepressants.
• If you have Crohn's disease (a chronic disease in which the immune system attacks the intestine, causing inflammation that usually produces bloody diarrhea) or ulcerative colitis, as medications like ibuprofen (arginine) may worsen these conditions.
• If you are being treated with diuretics (medications to increase urine production), as your doctor should monitor your kidney function.
• If you have systemic lupus erythematosus (a chronic disease that affects the immune system and can affect various vital organs, the nervous system, blood vessels, skin, and joints), as it may cause aseptic meningitis (inflammation of the meninges that protect the brain and spinal cord, not caused by bacteria).
• If you have acute intermittent porphyria (a metabolic disease that affects your blood and can cause symptoms such as reddish urine color, blood in urine, or liver disease), so that your doctor can assess the convenience or not of treatment with ibuprofen.
• If you experience headaches after prolonged treatment, do not take higher doses of the medication.

• If you experience vision changes during treatment with ibuprofen, discontinue treatment and consult your doctor for an ophthalmological examination.

• It is possible that allergic reactions may occur with this medication. Treatment should be discontinued if redness and inflammation or skin injury appear.
• Skin reactions: Serious skin reactions have been reported with Espidifen. Stop taking Espidifen and consult your doctor immediately if you experience any skin rash, mucous membrane lesions, blisters, or other signs of allergy, as these may be the first signs of a severe skin reaction. See section 4.
• Your doctor will perform stricter monitoring if you receive ibuprofen after undergoing major surgery.
• It is advisable not to take this medication if you have chickenpox.

It is important to use the smallest dose that relieves/control pain and not to take this medication for longer than necessary to control your symptoms.

Avoid taking it together with other NSAIDs, including COX-2 inhibitors.

Be careful with Espidifen:

Serious skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported in association with ibuprofen treatment. Discontinue Espidifen and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions described in section 4.

Precautions in Elderly Patients

Elderly patients have a higher frequency of adverse reactions to NSAIDs (non-steroidal anti-inflammatory drugs), especially gastrointestinal bleeding and perforation, which can be fatal.

Cardiovascular Precautions

Anti-inflammatory/analgesic medications like ibuprofen may be associated with a small increased risk of heart attack or stroke, especially when used in high doses.

Do not exceed the recommended dose or treatment duration.

You should discuss your treatment with your doctor or pharmacist before taking Espidifen if:

• You have heart problems, including heart failure, angina (chest pain), or if you have had a heart attack, bypass surgery, peripheral arteriopathy (circulation problems in the legs or feet due to narrowing or blockage of the arteries), or any type of stroke (including a "mini-stroke" or transient ischemic attack "TIA").
• You have high blood pressure, diabetes, high cholesterol, a family history of heart disease or stroke, or if you are a smoker.

Similarly, these types of medications can cause fluid retention, especially in patients with heart failure and/or high blood pressure (hypertension).

Ibuprofen has been reported to cause allergic reactions to this medication, such as respiratory problems, facial and neck swelling (angioedema), and chest pain. Stop using this medication immediately and contact your doctor or emergency medical services if you observe any of these signs.

Respiratory Disorders

Ibuprofen should be used with caution when administered to patients who have or have a history of bronchial asthma, chronic rhinitis, or allergic diseases, as ibuprofen has been reported to cause bronchospasm, urticaria, or angioedema in these patients.

Children and Adolescents

There is a risk of kidney failure in dehydrated children and adolescents.

The use of this medication is not recommended in children and adolescents weighing less than 40 kg or under 12 years of age, as the dose of ibuprofen it contains is not suitable for the recommended dosage in this group of patients.

Precautions during Pregnancy and in Women of Childbearing Age

Since the administration of medications like Ibuprofen (Arginine) has been associated with an increased risk of congenital anomalies/abortions, it is not recommended to administer it during the first and second trimester of pregnancy unless it is strictly necessary and advised by your doctor.

If you need treatment during this period or while trying to become pregnant, you should use the lowest dose for the shortest possible time.

If you take it for a few days from the 20th week of gestation onwards, Espidifen may cause kidney problems in your baby, which can lead to low levels of amniotic fluid surrounding the baby (oligohydramnios) or narrowing of a blood vessel (ductus arteriosus) in the baby's heart. If you need treatment for a few more days, your doctor may recommend additional monitoring.

In the third trimester, the administration of Ibuprofen (Arginine) is contraindicated.

For women of childbearing age, it should be noted that medications like Ibuprofen (Arginine) have been associated with a decrease in fertility.

Interference with Analytical Tests

• Bleeding time (may be prolonged for 1 day after discontinuing treatment)
• Blood glucose concentration (may decrease)
• Creatinine clearance (may decrease)
• Hematocrit or hemoglobin (may decrease)
• Blood urea nitrogen and serum creatinine and potassium concentrations (may increase)
• Liver function tests: increased transaminase values.

If you are going to undergo any diagnostic test (including blood tests, urine tests, skin tests using allergens, etc.), inform your doctor that you are taking this medication, as it may alter the results.

Use of Espidifen with Other Medications

Inform your doctor or pharmacist if you are using, have recently used, or may need to use any other medication.

Espidifen may affect or be affected by other medications. For example:

• Anticoagulant medications (e.g., to treat coagulation problems/prevent coagulation, e.g., aspirin, warfarin, ticlopidine).
• Medications that lower high blood pressure (ACE inhibitors such as captopril, beta-blockers such as atenolol, and angiotensin-II receptor antagonists such as losartan).

The following medications may interfere and should not be taken with Espidifen without consulting your doctor:

• Aspirin or other anti-inflammatory/analgesic agents: increase the risk of gastrointestinal ulcers and bleeding.
• Antihypertensives (beta-blockers, ACE inhibitors, and angiotensin II antagonists) and diuretics: NSAIDs may reduce the effect of diuretics and other antihypertensive agents. Concomitant administration of ibuprofen and potassium-sparing diuretics may cause hyperkalemia and increase the risk of renal toxicity.
• Antiplatelet agents (prevent the formation of blood clots or thrombi in blood vessels) such as ticlopidine.
• Anticoagulants (medications used to "thin" the blood and prevent the formation of clots) such as warfarin.
• Lithium (medication used to treat depression). Your doctor may adjust the dose of this medication.
• Methotrexate. Your doctor may adjust the dose of this antimetabolite medication (slows down the growth of certain cells produced by the body).
• Mifepristone (abortion inducer).
• Digoxin and cardiac glycosides (used to treat heart disorders).
• Hydantoins such as phenytoin (used to treat epilepsy).
• Sulfonamides such as sulfamethoxazole and cotrimoxazole (used to treat certain bacterial infections).
• Corticosteroids such as cortisone and prednisolone.
• Diuretics (medications used to increase urine production).
• Pentoxifylline (to treat intermittent claudication).
• Probenecid (used in patients with gout or with penicillin in infections).
• Antibiotics of the quinolone group such as norfloxacin.
• Sulfinpyrazone (for gout).
• Sulfonylureas such as tolbutamide or insulin (for diabetes), may require dose adjustment.
• Certain antidepressants (selective serotonin reuptake inhibitors).
• Tacrolimus (used in organ transplants to prevent rejection).
• Zidovudine (medication against the AIDS virus).
• Thrombolytics (medications that dissolve blood clots).
• Aminoglycoside antibiotics such as neomycin.
• Herbal extracts: Ginkgo biloba tree.
• CYP2C9 inhibitors (responsible for the metabolism of numerous medications in the liver), such as voriconazole and fluconazole (used to treat fungal infections).

Other medications may also affect or be affected by treatment with Espidifen. Therefore, you should always consult your doctor or pharmacist before using Espidifen with other medications.

Taking Espidifen with Food, Drinks, and Alcohol

3. How to take Espidifen

Follow the administration instructions for this medication exactly as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again.

Your doctor will indicate the duration of treatment with Espidifen. Do not suspend treatment beforehand, as this will not achieve the expected results. Similarly, do not use this medication for longer than indicated by your doctor.

The lowest effective dose should be used for the shortest time necessary to relieve symptoms. If you have an infection, consult a doctor without delay if symptoms (such as fever and pain) persist or worsen (see section 2).

This medication is administered orally.

Patients with stomach discomfort should take the medication with milk or during/after meals.

Adults and adolescents

In adults and adolescents from 12 to 18 years old, take one sachet (400 mg) every 6 to 8 hours, depending on the intensity of the condition and response to treatment.

In some cases, higher doses may be required, but in any case, it is recommended not to exceed the maximum daily dose of 2,400 mg in adults and 1,600 mg in adolescents from 12 to 18 years old.

Use in elderly patients

If you are over 60 years old, your doctor may prescribe a lower dose than usual. If so, the dose can only be increased once your doctor has checked that you tolerate the medication well.

Use in patients with kidney and/or liver disease

If you have kidney and/or liver disease, your doctor may prescribe a lower dose than usual. If so, take the exact dose prescribed by your doctor.

If you think the effect of Espidifen is too strong or too weak, inform your doctor or pharmacist.

Use in children

The use of this medication is not recommended in children and adolescents weighing less than 40 kg or under 12 years old, as the dose of ibuprofen it contains is not suitable for the recommended dosage in this group of patients.

If you take more Espidifen than you should

In case of overdose or accidental ingestion, consult a doctor or pharmacist immediately, go to the nearest hospital, or call the Toxicology Information Service (telephone: 91.5620420) indicating the medication and the amount ingested, to inform about the risk and ask for advice on the measures to be taken.

The symptoms of overdose may include nausea, stomach pain, vomiting (which may be bloody), gastrointestinal bleeding (see also section 4 below), diarrhea, headache, ringing in the ears, confusion, and tremulous eye movement. Agitation, drowsiness, disorientation, or coma may also occur. Occasionally, patients develop convulsions. At high doses, somnolence, chest pain, palpitations, loss of consciousness, convulsions (mainly in children), weakness, and dizziness, blood in the urine, low potassium levels in the blood, feeling of cold body, and respiratory problems have been reported. Additionally, the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating coagulation factors. Acute renal failure and liver damage may occur. An exacerbation of asthma in asthmatics is possible. Additionally, there may be low blood pressure and difficulty breathing.

In case of ingestion of significant amounts, activated charcoal should be administered. Gastric lavage will be considered if significant amounts have been ingested and within 60 minutes following ingestion.

If you forget to take Espidifen

Do not take a double dose to make up for the forgotten dose.

If you forget to take your corresponding dose, take it as soon as you remember. However, if the time for the next dose is near, skip the forgotten dose and take the next dose at the usual time.

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medications, this medication can cause adverse effects, although not all people suffer from them.

Adverse effects of medications like Espidifen are more common in people over 65 years old.

The incidence of adverse effects is lower in short treatments and if the daily dose is below the maximum recommended dose.

Frequencies are established according to the following classification: very frequent (may affect more than 1 in 10 patients); frequent (may affect up to 1 in 10 patients); uncommon (may affect up to 1 in 100 patients); rare (may affect up to 1 in 1,000 patients); very rare (may affect up to 1 in 10,000 patients); frequency unknown (cannot be estimated from available data).

The following adverse effects have been observed:

Infections and infestations

Very rare: Exacerbation of inflammation-related infections (e.g., development of necrotizing fasciitis) coinciding with the use of non-steroidal anti-inflammatory drugs.

Note: If signs of infection or worsening occur during treatment with ibuprofen, it is recommended to go to the doctor immediately, in case antibiotic therapy needs to be initiated.

Blood and lymphatic system disorders

Rare: Aplastic anemia (bone marrow failure to produce different types of cells).

Very rare: Decreased platelets, decreased white blood cells (may manifest as frequent infections with fever, chills, or sore throat), decreased red blood cells (may manifest as difficulty breathing and pale skin), decreased granulocytes (a type of white blood cell that can predispose to infections), pancytopenia (deficiency of red, white, and blood platelets), agranulocytosis (very significant decrease in granulocytes), hemolytic anemia (premature destruction of red blood cells). The first symptoms are: fever, sore throat, superficial ulcers in the mouth, flu-like symptoms, extreme fatigue, nosebleeds, and skin bleeding. Prolongation of bleeding time.

Immune system disorders

Uncommon: Allergic reaction, hypersensitivity reactions with skin rash and itching, as well as asthma attacks (possibly along with a drop in blood pressure).

Rare: Anaphylaxis (generalized allergic reaction).

Very rare: Severe hypersensitivity reactions (these can be characterized by swelling of the face, tongue, and larynx with bronchospasm, dyspnea, tachycardia, and hypotension that can include potentially fatal shock).

Note: In the event of these symptoms, which can occur with the first use, immediate medical attention is required.

Psychiatric disorders

Uncommon: Insomnia, anxiety, restlessness.

Rare: Psychotic reaction, nervousness, irritability, depression, confusion, disorientation.

Nervous system disorders

Frequent: Fatigue or drowsiness, headache, and dizziness or feeling of instability.

Uncommon: Insomnia, excitement, irritability.

Rare: Paresthesia (sensation of numbness, tingling, prickling, etc., more frequent in hands, feet, arms, or legs).

Very rare: Aseptic meningitis. In most cases where aseptic meningitis has been reported with ibuprofen, the patient suffered from some form of autoimmune disease (such as systemic lupus erythematosus or other collagen diseases), which was a risk factor. The symptoms of aseptic meningitis observed were neck stiffness, headache, nausea, vomiting, fever, or disorientation.

Eye disorders

Uncommon: Vision disturbances.

Rare: Abnormal or blurred vision.

Frequency unknown: Papilledema (inflammation of the optic nerve).

Ear and labyrinth disorders

Frequent: Vertigo.

Uncommon: Ringing or buzzing in the ears.

Rare: Hearing difficulty.

Cardiac disorders

Medications like Espidifen may be associated with a moderate increase in the risk of suffering a heart attack ("myocardial infarction") or stroke.

Very rare: Palpitations, heart failure.

Frequency unknown: Heart failure, chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome.

Vascular disorders

Edema (fluid retention), arterial hypertension, and heart failure have also been observed in association with treatments with medications of the ibuprofen type (arginine).

Very rare: Arterial hypertension.

Frequency unknown: Arterial thrombosis.

Respiratory disorders

Uncommon: Asthma, worsening of asthma, bronchospasm, dyspnea (difficulty breathing).

Frequency unknown: Throat irritation.

Gastrointestinal disorders

The most frequent adverse effects that occur with medications like Espidifen are gastrointestinal: peptic ulcers, gastrointestinal bleeding, perforations (in some cases fatal, especially in elderly patients).

Frequent: Gastrointestinal disorders such as heartburn (acidity, reflux), abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, and mild gastrointestinal bleeding that can cause anemia in exceptional cases.

Uncommon: Gastrointestinal ulcers, potentially with bleeding and perforation, ulcerative stomatitis, exacerbation of colitis and Crohn's disease, melena (blood in stool), gastritis.

Rare: Vomiting blood.

Very rare: Esophageal inflammation, pancreatitis, intestinal stenosis.

Frequency unknown: Anorexia.

Hepatobiliary disorders

Rare: Liver damage, hepatitis (inflammation of the liver), liver function abnormalities, and jaundice (yellowing of the skin and eyes).

Skin and subcutaneous tissue disorders

Frequent: Skin rash.

Uncommon: Skin redness, itching or skin swelling (angioedema, urticaria), purpura (purple spots on the skin).

Rare: Anaphylactic reaction.

Very rare: Medications like Espidifen may be associated, in very rare cases, with severe blistering reactions such as Stevens-Johnson syndrome (widespread erosions affecting the skin and two or more mucous membranes and purple-colored lesions, preferably on the trunk) and toxic epidermal necrolysis (erosions on mucous membranes and painful lesions with necrosis and shedding of the epidermis). Hair loss, erythema multiforme (skin lesion), exceptionally severe skin infections and soft tissue complications can occur during chickenpox.

Frequency unknown: Photosensitivity (skin reactions due to light influence), worsening of skin reactions. A severe skin reaction known as DRESS syndrome can occur. The symptoms of DRESS syndrome include: skin rash, lymph node inflammation, and elevated eosinophils (a type of white blood cell), generalized red scaly rash, with bumps under the skin and blisters located mainly in skin folds, trunk, and upper limbs, accompanied by fever at the start of treatment (acute generalized exanthematous pustulosis). Stop taking Espidifen if you present these symptoms and seek immediate medical attention. See also section 2.

Renal and urinary disorders

Rare: Hematuria (blood in the urine).

Very rare: Edema (signs that may indicate kidney disease, which can sometimes include kidney failure); kidney tissue damage (papillary necrosis), increased serum uric acid concentration.

Based on experience with non-steroidal anti-inflammatory drugs in general, cases of interstitial nephritis, nephrotic syndrome, and kidney failure cannot be excluded.

General disorders

Very rare: Worsening of inflammation during infectious processes.

Frequency unknown: Edema.

Investigations

Rare: Alteration of liver function tests.

Frequency unknown: Alteration of kidney function tests.

To date, no serious allergic reactions have been reported with Espidifen, although they cannot be ruled out. The manifestations of this type of effect could be fever, skin rash, abdominal pain, severe and persistent headache, nausea, vomiting, angioedema, swelling of the face, tongue, and throat, difficulty breathing, asthma, palpitations, hypotension, or shock.

If any of the following adverse effects occur, interrupt treatment and go to your doctor immediately:

• Allergic reactions such as skin rashes, swelling of the face, wheezing in the chest, or difficulty breathing.
• Vomiting blood or coffee grounds-like vomit.
• Blood in the stool or bloody diarrhea.
• Severe stomach pain.
• Blisters or significant skin peeling.
• Severe or persistent headache.
• Yellowing of the skin (jaundice).
• Signs of severe hypersensitivity (see above in this section).
• Swelling of the limbs or fluid accumulation in the arms or legs.
• Vision disturbances.

Interrupt treatment with Espidifen and seek immediate medical attention if you notice any of the following symptoms:

• Reddish, non-raised, target-like, or circular spots on the trunk, often with blisters in the center, skin peeling, mouth, throat, nose, genital, and eye ulcers. These severe skin rashes can be preceded by fever and flu-like symptoms [exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis].
• Generalized skin rash, elevated body temperature, and swollen lymph nodes (DRESS syndrome).
• Generalized red scaly rash, with bumps under the skin and blisters, accompanied by fever. The symptoms usually appear at the start of treatment (acute generalized exanthematous pustulosis).

Reporting adverse effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medications: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

5. Conservation of Espidifen

Keep out of sight and reach of children.

No special storage conditions are required.

Do not use this medication after the expiration date shown on the packaging after the abbreviation CAD. The expiration date is the last day of the month indicated.

Medications should not be thrown down the drain or into the trash. Deposit the packaging and medications you no longer need in the SIGRE point of your usual pharmacy. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This way, you will help protect the environment.

6. Package contents and additional information

Composition of Espidifen

The active ingredient is ibuprofen. Each sachet contains 400 mg of ibuprofen (as 770 mg of ibuprofen arginine).

The other components (excipients) are: aspartame (E951), sucrose, sodium hydrogen carbonate, sodium saccharin, peppermint flavor, and anise flavor (contains butylhydroxyanisole (E 320)). See section 2. "Espidifen contains aspartame, sucrose, butylhydroxyanisole (E 320), and sodium".

Appearance of Espidifen and package contents

Oral solution granules, white in color.

Each package contains 30 sachets with granules.

Marketing authorization holder

Zambon, S.A.U.

Maresme, 5. Can Bernades-Subirà Industrial Estate

08130 Sta. Perpètua de Mogoda (Barcelona)

Spain

Manufacturer

Zambon, S.p.A.

Via della Chimica, 9

36100 Vicenza

Italy

or

Zambon, S.A.U.

Maresme, 5. Can Bernades-Subirà Industrial Estate

08130 Sta. Perpètua de Mogoda (Barcelona)

Spain

Date of the last revision of this prospectus:November 2024

Detailed and updated information on this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/