Difenadol 400 mg film-coated tablets: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Difenadol 400 mg film-coated tablets

ibuprofen

Read the entire leaflet carefully before you start taking this medicine, because it contains important information for you.

Follow exactly the instructions for use of the medicine contained in this leaflet or as indicated by your doctor or pharmacist.

Keep this leaflet, as you may need to read it again.
If you need advice or more information, consult your pharmacist.
If you experience adverse effects, consult your doctor or pharmacist, even if they are adverse effects not listed in this leaflet. See section 4.
You must consult a doctor if you worsen or do not improve after 3 days if you have fever or 4 days for pain treatment in the case of an adult. You must consult a doctor if you worsen or do not improve after 3 days in the case of an adolescent.

Contents of the leaflet

What Difenadol is and what it is used for
What you need to know before taking Difenadol
How to take Difenadol
Possible side effects
How to store Difenadol
Contents of the pack and other information

1. What Difenadol is and what it is used for

Difenadol contains the active substance ibuprofen. Ibuprofen is a medicine that reduces fever and relieves pain (non-steroidal anti-inflammatory drug, NSAID).

In adults and adolescents weighing 40 kg or more (12 years of age and older), it is used for the short-term symptomatic treatment of mild to moderate pain and/or fever.

2. What you need to know before starting to take Difenadol

Active substance: Difenadol (Diphenadol)

Indications: Difenadol is indicated for the symptomatic treatment of nausea and vomiting.

Contraindications:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant use with drugs that prolong the QT interval or induce torsades de pointes (e.g., Class Ia and III antiarrhythmics, antipsychotics, antidepressants, macrolide antibiotics, antimalarials).
Known QT interval prolongation or history of torsades de pointes.
Severe hepatic impairment.
Use in children under 18 years of age (due to lack of data on safety and efficacy).
Pregnancy and lactation (see section 4.6).

Special warnings and precautions for use:

Use with caution in patients with:
- History of cardiac arrhythmias.
- Electrolyte imbalances (e.g., hypokalemia, hypomagnesemia).
- Concomitant use of other medications that may prolong the QT interval.
Monitor ECG in patients at risk of QT prolongation.
Avoid alcohol consumption during treatment, as it may enhance central nervous system depression.
May cause drowsiness; caution is advised when driving or operating machinery.

Interactions:

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) may increase plasma concentrations of difenadol.
CYP3A4 inducers (e.g., rifampicin, carbamazepine, St. John’s wort) may reduce its efficacy.
Concomitant use with other centrally acting drugs (e.g., sedatives, opioids, anxiolytics) may potentiate CNS depression.

Fertility, pregnancy and lactation:

Pregnancy: Avoid use during pregnancy unless clearly necessary. No adequate data on human fetal effects.
Lactation: Not recommended. It is unknown whether difenadol is excreted in human milk.
Fertility: No human data available.

Effects on ability to drive and use machines:
Difenadol may impair cognitive function and reaction time. Patients should be advised not to drive or operate machinery if affected.

Overdose:
Symptoms may include severe drowsiness, respiratory depression, hypotension, and QT prolongation. Treatment is symptomatic and supportive. No specific antidote is known. Consider activated charcoal if ingestion is recent. Hemodialysis is unlikely to be effective due to high protein binding.

For further information, refer to the full Summary of Product Characteristics.

Do not take Difenadol

If you are allergic (hypersensitive) to ibuprofen or to any of the other components of this medicine (listed in section 6). Signs of allergy may include: swelling of the eyelids, lips, tongue, or throat.
If you have ever had an allergic reaction (such as bronchospasm (tightening of the muscles in the lungs that may cause difficulty breathing), asthma (nasal discharge, itching, and inflammation of the nasal passages with sneezing), urticaria (a type of skin rash), or angioedema (swelling beneath the skin)) after taking ibuprofen, acetylsalicylic acid, or other similar painkillers (NSAIDs).
If you have bleeding disorders or blood coagulation problems.
If you have an active ulcer or a history of recurrent stomach/duodenal ulcer (peptic ulcer) or gastrointestinal bleeding (two or more episodes of proven ulceration or bleeding).
If you have a history of gastrointestinal bleeding or perforation related to previous treatment with NSAIDs.
If you have cerebral hemorrhage or other active bleeding.
If you have severe liver, kidney, or 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

Adverse reactions are minimized by using the lowest effective dose for the shortest possible duration.

You should consult your doctor or pharmacist before taking Difenadol:

If you have systemic lupus erythematosus (SLE), sometimes known as lupus, or a connective tissue disease (autoimmune diseases affecting connective tissue).
If you have or have had intestinal disease (ulcerative colitis or Crohn's disease), as your condition may worsen.
If you have hereditary disorders in blood formation (e.g., acute intermittent porphyria).
If you have reduced liver or kidney function.
After undergoing major surgery.
If you are sensitive (allergic) to other substances.
If you suffer from hay fever (pollen allergy), nasal polyps, or chronic obstructive respiratory disorders, you have an increased risk of allergic reactions. These allergic reactions may manifest as asthma attacks (referred to as analgesic-induced asthma), Quincke's edema (angioedema), or urticaria.
If you are dehydrated.
If you have an infection; see the section "Infections" below.

Effects on the gastrointestinal tract

The combined use of ibuprofen with other non-steroidal anti-inflammatory drugs (NSAIDs), including so-called COX-2 inhibitors (cyclooxygenase-2 inhibitors), should be avoided.

Gastrointestinal bleeding, ulcers, and perforation:

Cases of gastrointestinal bleeding, ulcers, and perforation (which may be fatal) have been reported during treatment with NSAIDs. These may occur at any time during treatment, with or without previous warning symptoms, and with or without a prior history of serious gastrointestinal events.

The risk of gastrointestinal bleeding, ulcers, and perforation increases with higher NSAID doses and is greater in patients with a history of ulcers, especially those with complications such as bleeding or perforation (see section 2 "Do not take Difenadol") and in elderly patients. These patients should start treatment with the lowest available dose.

For these patients, as well as for those requiring additional treatment with low-dose acetylsalicylic acid or other medications that may increase the risk of gastrointestinal disorders, your doctor may consider adding a stomach-protective agent (e.g., misoprostol or proton pump inhibitors).

If you have a history of adverse gastrointestinal reactions—especially in elderly patients—consult your doctor if you experience unusual abdominal symptoms (particularly gastrointestinal bleeding), especially at the beginning of therapy.

Caution is advised if you are also taking other medications that may increase the risk of ulcers or bleeding, e.g., oral corticosteroids, anticoagulants (such as warfarin), selective serotonin reuptake inhibitors (used to treat psychiatric disorders, including depression), or platelet aggregation inhibitors such as acetylsalicylic acid (see section 2 "Other medicines and Difenadol").

You should discontinue treatment and consult a doctor immediately if you develop gastrointestinal bleeding or ulcers during treatment with Difenadol.

Effects on the cardiovascular system

Anti-inflammatory/analgesic medicines such as ibuprofen may be associated with a small increased risk of heart attack or stroke, especially when used at high doses. Do not exceed the recommended dose or duration of treatment.

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

You have heart problems, including heart failure, angina (chest pain), or have had a heart attack, bypass surgery, peripheral arterial disease (circulation problems in the legs or feet due to narrowed or blocked 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.

Serious adverse cutaneous reactions (SACRs)

Serious skin reactions have been reported, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), in association with ibuprofen treatment. Discontinue treatment with Difenadol and seek immediate medical attention if you notice any symptoms related to these serious skin reactions described in section 4. If you have chickenpox, it is advisable to avoid using ibuprofen.

Infections

Difenadol may mask signs of infection such as fever and pain. Therefore, Difenadol may delay appropriate treatment of the infection, increasing the risk of complications. This has been observed in bacterial pneumonia and bacterial skin infections associated with chickenpox. If you take this medicine while having an infection and infection symptoms persist or worsen, consult a doctor without delay.

Other warnings

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. At the first signs of a hypersensitivity reaction after taking ibuprofen, treatment must be discontinued and you should consult your doctor. Medically required measures, appropriate to the symptoms, should be initiated by trained medical personnel.

Ibuprofen may reversibly inhibit platelet aggregation and platelet function. Therefore, patients with coagulation disorders should be carefully monitored.

Regular monitoring of liver function tests, kidney function, and blood counts is required during prolonged use of ibuprofen.

Prolonged use of any type of painkiller for headache may worsen it. If this situation is observed or suspected, consult a doctor and discontinue treatment.

In general, habitual use of different types of painkillers may lead to serious kidney problems with risk of renal failure (analgesic nephropathy). This risk may increase during physical exertion associated with salt loss and dehydration. Therefore, it should be avoided.

The risk of renal failure increases in dehydrated patients, elderly patients, and those taking diuretics and ACE inhibitors.

If you experience vision problems, please consult your doctor.

Signs of an allergic reaction to ibuprofen, including difficulty breathing, swelling of the face and neck area (angioedema), and chest pain, have been reported. Immediately discontinue treatment with ibuprofen and contact your doctor or emergency medical services as soon as possible if you notice any of these signs.

Elderly patients

Elderly patients have a higher frequency of adverse reactions to NSAIDs (non-steroidal anti-inflammatory drugs), especially gastrointestinal bleeding and perforation, which may be fatal (see also the warning on bleeding at the beginning of section 2).

Adolescents

There is a risk of renal failure in dehydrated adolescents.

Other medicines and Difenadol

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

Difenadol may interact with or be affected by other medicines. For example:

Digoxin, phenytoin, and lithium: Combining ibuprofen with digoxin (used for heart failure), phenytoin (used to treat seizures/epilepsy), or lithium (used to treat, for example, depression) may increase blood levels of these medicines. Monitoring of serum lithium levels is required. Generally, monitoring of serum digoxin and phenytoin levels is not required when used according to indications (3 or 4 days maximum).
Anticoagulants (to thin the blood/prevent blood clots, e.g., acetylsalicylic acid, warfarin, ticlopidine): NSAIDs may enhance the effects of anticoagulants such as warfarine.
Diuretics and antihypertensive medicines:

Difenadol may reduce the effect of medicines used to increase urine production (diuretics) and lower blood pressure (antihypertensive medicines, e.g., ACE inhibitors, beta-blockers, and angiotensin II receptor antagonists). Combined administration of ibuprofen and potassium-sparing diuretics (medicines used to increase urine elimination) may lead to increased potassium levels in the blood.

Medicines that lower high blood pressure (ACE inhibitors such as captopril, beta-blockers such as atenolol, and angiotensin II receptor antagonists such as losartan): ibuprofen may reduce the effect of ACE inhibitors (used to treat heart failure and hypertension). In addition, combined use increases the risk of kidney dysfunction.
Cholestyramine (a medicine used to lower cholesterol) combined with ibuprofen may reduce ibuprofen absorption in the gastrointestinal tract. However, the clinical significance is unknown.
Other analgesics: combining ibuprofen with other NSAIDs and analgesics, including COX-2 inhibitors (e.g., celecoxib), may increase the risk of gastrointestinal ulcers and bleeding.
Platelet aggregation inhibitors and certain antidepressants (selective serotonin reuptake inhibitors/SSRIs) may increase the risk of gastrointestinal bleeding.
Metotrexate: administering ibuprofen within 24 hours before or after metotrexate (used to treat certain types of cancer and rheumatism) may increase metotrexate concentrations and its side effects.
Cyclosporine and tacrolimus: there is an increased risk that immunosuppressive medicines such as cyclosporine and tacrolimus may damage the kidneys.
Probenecid or sulfinpyrazone: medicines containing probenecid or sulfinpyrazone (used in patients with gout) may delay ibuprofen excretion. This may cause ibuprofen to accumulate in the body, increasing its side effects.
Sulfonylureas: when combining ibuprofen with sulfonylureas (medicines used to treat diabetes), blood sugar levels should be monitored.
Zidovudine: evidence suggests an increased risk of hemarthrosis (blood accumulation in joints) and bruising (hematomas) in HIV-positive hemophiliacs using zidovudine (an anti-AIDS virus medicine) with ibuprofen.
Quinolone antibiotics: the risk of seizures (fits) may increase when quinolone antibiotics such as ciprofloxacin are taken together with ibuprofen.
Aminoglycosides: combined use of ibuprofen with aminoglycosides (a type of antibiotic) and NSAIDs may reduce aminoglycoside elimination.
Voriconazole and fluconazole (CYP2C9 inhibitors) used for fungal infections, as the effect of ibuprofen may be enhanced. A reduction in ibuprofen dose should be considered, particularly when a high dose of ibuprofen is administered with voriconazole or fluconazole.
Ginkgo biloba (a herbal medicine) may increase the risk of bleeding with NSAIDs.
Mifepristone: combining mifepristone with other NSAIDs and analgesics (i.e., ibuprofen) may reduce the effect of mifepristone.
Ritonavir: combined use with ritonavir (an antiviral medicine used to treat HIV infections) may increase plasma concentrations of NSAID analgesics.
Alcohol, bisphosphonates, and oxpentifylline (pentoxifylline): combining ibuprofen with alcohol, bisphosphonates (used for osteoporosis), or pentoxifylline (to treat peripheral arterial circulatory problems) may increase gastrointestinal side effects and the risk of bleeding and ulcers.
Baclofen (a muscle relaxant) due to the high toxicity of baclofen.
Medicines for treating inflammation (corticosteroids) due to the increased risk of gastrointestinal ulcers or bleeding.

Other medicines may also affect or be affected by ibuprofen treatment. Therefore, always consult your doctor or pharmacist before using ibuprofen with other medicines.

Taking Difenadol with alcohol

Adverse reactions to ibuprofen may be increased when alcohol is consumed, especially those affecting the central nervous system and gastrointestinal tract. You should not drink alcohol while taking ibuprofen.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

Do not take this medicine during the last 3 months of pregnancy, as it may harm the fetus or cause problems during delivery. It may cause kidney and heart problems in your fetus. It may affect your and your baby's tendency to bleed and may delay or prolong labor more than expected.

Do not take this medicine during the first 6 months of pregnancy unless clearly necessary and as directed by your doctor.

If treatment is needed during this period or while trying to conceive, you should take the lowest possible dose for the shortest possible time. From week 20 of pregnancy, if this medicine is taken for more than a few days, it may cause kidney problems in your fetus, leading to low levels of amniotic fluid surrounding the baby (oligohydramnios), or narrowing of a blood vessel (ductus arteriosus) in the baby's heart. If treatment is needed for longer than a few days, your doctor may recommend additional monitoring.

Breastfeeding

Small amounts of ibuprofen pass into breast milk. However, as no harmful effects on infants have been reported to date, breastfeeding usually does not need to be interrupted during short-term use of ibuprofen at the recommended dose for fever and pain.

Fertility

This product belongs to the group of NSAIDs that may affect fertility in women. This effect is reversible upon discontinuation of the medication. Consult your doctor if you plan to become pregnant or have difficulty conceiving.

Driving and use of machines

Ibuprofen generally has no or negligible influence on the ability to drive or operate machinery. However, at higher doses, adverse effects such as fatigue and dizziness may occur, potentially affecting reaction ability while driving or operating machinery. This is especially important when the medicine is combined with alcohol.

Difenadol contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per tablet; hence, it is essentially "sodium-free".

3. How to take Difenadol

Follow exactly the instructions for use of this medicine given by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist again.

The lowest effective dose should be used for the shortest duration 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).

The usual dose is:

Adults and adolescents weighing 40 kg or more (12 years of age or older):

One tablet (400 mg) as a single dose.

The dosing interval should be chosen according to observed symptoms and the recommended maximum daily dose. The interval between doses should not be less than 6 hours. Do not take more than 3 tablets (1,200 mg) of ibuprofen within a 24-hour period.

This medicine is not recommended for use in adolescents weighing less than 40 kg or in children under 12 years of age.

Adverse reactions can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms.

If you have severe hepatic or renal disease or are elderly, your doctor will determine the correct dose for you, which will be the lowest possible dose.

Method of administration

Oral use.

Take the tablet with a glass of water.

Ibuprofen tablets should be swallowed whole, without chewing, crushing, or sucking, to avoid mouth discomfort or throat irritation.

Patients with a sensitive stomach are advised to take ibuprofen with food. Difenadol is intended for short-term use only.

For adults

If you require this medicine for more than 3 days to treat fever or for more than 4 days to treat pain, or if symptoms worsen, you must consult a doctor.

For adolescents

If adolescents require this medicine for more than 3 days, or if symptoms worsen, they must consult a doctor.

If you take more Difenadol than you should

If you have taken more ibuprofen than you should, or if a child has accidentally ingested the medicine, contact your doctor or pharmacist immediately or call the Toxicology Information Service at telephone number: 91 562 04 20, indicating the medicine and the amount ingested, or go to the nearest hospital to obtain information on the risk and advice on the measures to be taken.

Symptoms of overdose may include nausea, stomach pain, vomiting (which may contain blood-stained sputum), gastrointestinal bleeding (see also section 4 below), diarrhea, headache, tinnitus, confusion, and involuntary eye movements.

In addition, blurred vision and worsening of asthma in asthmatic patients may occur.

Nervousness, drowsiness, disorientation, or coma may also occur. Occasionally, patients may develop seizures.

At high doses, symptoms such as drowsiness, excitement, disorientation, chest pain, palpitations, loss of consciousness, seizures (mainly in children), weakness, dizziness, blood in the urine, low blood potassium levels, low blood pressure, prolonged prothrombin time/INR (likely due to interference with circulating coagulation factors), acute kidney failure, liver damage, respiratory depression, cyanosis, decreased body temperature, breathing problems with reduced respiration, and chills have been reported.

If you forget to take Difenadol

Do not take a double dose to make up for missed doses.

If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

The most commonly observed adverse effects involve the gastrointestinal tract. Gastric/duodenal ulcers (peptic ulcers), perforation, or bleeding—sometimes fatal—may occur, particularly in elderly patients (see section 2: "Warnings and precautions"). Nausea, vomiting, diarrhea, flatulence, constipation, indigestion, abdominal pain, blood in stools, vomiting blood, and ulcerative lesions (ulcers) in the mouth and throat area (ulcerative stomatitis) may also occur. Exacerbation of colitis and Crohn's disease (see section 2: "Warnings and precautions") has been reported after use. Gastritis has been observed less frequently. In particular, the risk of developing gastrointestinal bleeding depends on the dose level and duration of treatment.

Inflammation (edema), high blood pressure (hypertension), and heart failure have been observed in association with treatment with NSAIDs.

More serious adverse effects

Stop treatment with ibuprofen and seek immediate medical attention if you notice the following symptoms:
Flat, red, target-like or circular skin rashes on the trunk, often with blisters in the center, skin peeling, and ulcers in the mouth, throat, nose, genitals, or eyes. These severe skin rashes may be preceded by fever and flu-like symptoms [exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis].
Widespread rash, high body temperature, and swollen lymph nodes (DRESS syndrome).
Generalized, red, scaly rash with bumps under the skin and blisters, accompanied by fever. Symptoms usually appear at the beginning of treatment (acute generalized exanthematous pustulosis).
Stop treatment and consult your doctor immediately if you develop severe allergic reactions (hypersensitivity), a very rare side effect (may affect up to 1 in 10,000 people):

These may include:

Swelling of the face (facial edema), tongue, or throat (laryngeal swelling with airway constriction).
Difficulty breathing.
Rapid heartbeat.
Drop in blood pressure leading to life-threatening shock.
You should contact your doctor immediately if you develop an infection with symptoms such as fever and severe deterioration in your general condition, or fever with signs of localized infection such as sore throat/pharynx/mouth or urinary problems. Ibuprofen may cause a decrease in white blood cells [agranulocytosis, a very rare adverse effect (may affect up to 1 in 10,000 people)] resulting in reduced resistance to infection. It is important to inform your doctor about your medication.
Very severe blistering reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and/or erythema multiforme [a very rare side effect (may affect up to 1 in 10,000 people)]. A serious skin reaction known as DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) may also occur. Symptoms of DRESS syndrome include: skin rash, fever, swollen lymph nodes, and elevated eosinophils (a type of white blood cell) [frequency not known (cannot be estimated from available data)]. Stop taking ibuprofen and contact a doctor immediately if you develop a skin rash or mucosal lesions. Severe rashes may include blisters on the skin, especially on the legs, arms, hands, and feet, and may involve the face and lips. A more severe skin reaction, toxic epidermal necrolysis (erosions of mucous membranes and painful lesions with necrosis and detachment of the epidermis), may occur.
Stop taking ibuprofen if you experience severe upper abdominal pain, vomiting blood, black stools, or bloody diarrhea, and inform your doctor immediately.
If you develop edema (fluid retention), especially in patients with high blood pressure (hypertension) or kidney problems, nephrotic syndrome, tubulointerstitial nephritis (a kidney disorder), which may be associated with acute renal failure (kidney failure) [very rare adverse effects (may affect up to 1 in 10,000 people)]. Decreased urine output, swelling due to fluid accumulation in tissues (edema), and malaise (generally feeling unwell) may be signs of kidney failure.

If you experience any of these adverse effects or if they worsen, stop treatment and consult your doctor immediately.

Other adverse effects

Frequent (may affect more than 1 in 10 people)

Gastrointestinal discomfort, heartburn, abdominal pain, nausea, vomiting, flatulence, diarrhea, constipation, indigestion, and mild gastrointestinal bleeding, which may exceptionally lead to anemia.

Uncommon (may affect up to 1 in 100 people)

Central nervous system disorders such as headache, dizziness, insomnia, restlessness, irritability, or fatigue.
Visual disturbances. In such cases, discontinue ibuprofen treatment and consult your doctor.
Especially in elderly patients: gastrointestinal ulcers, sometimes with bleeding and perforation (a hole in the intestinal wall), ulcerative stomatitis (inflammation of the oral mucosa with ulceration), stomach inflammation (gastritis), worsening of colitis and Crohn's disease, which may be fatal.
Inflammation of the stomach lining (gastritis).
Hypersensitivity reactions such as skin rash and itching, as well as asthma attacks (possibly with a drop in blood pressure).

Stop taking ibuprofen and inform your doctor immediately.

Rare (may affect up to 1 in 1,000 people)

Tinnitus (ringing in the ears).
Hearing loss.
Kidney damage (papillary necrosis), high blood levels of uric acid, elevated blood urea levels.

Very rare (may affect up to 1 in 10,000 people)

Blood cell formation disorders such as reduced red blood cells or hemoglobin (anemia), white blood cells (leukopenia), or platelet levels (thrombocytopenia); and other blood disorders (pancytopenia, agranulocytosis, eosinophilia, coagulopathy, neutropenia, aplastic anemia, or hemolytic anemia). Initial symptoms include: fever, sore throat, superficial mouth ulcers, flu-like symptoms, extreme fatigue, nosebleeds, and skin bleeding.
Worsening of infections-related inflammation (e.g., necrotizing fasciitis) has been reported with certain painkillers (NSAIDs). If symptoms of infection appear or worsen during ibuprofen treatment (e.g., redness, swelling, warmth, pain, fever), seek immediate medical attention. Anti-infective/antibiotic therapy should be considered.
Symptoms of aseptic meningitis (inflammation of the brain and its lining not caused by infection) have been observed during ibuprofen use, such as sudden severe headache, nausea, vomiting, fever, neck stiffness, or transient loss of consciousness. Patients with autoimmune disorders (SLE, mixed connective tissue disease) appear to be more susceptible.
Low blood sugar (hypoglycemia).
Low sodium levels in blood (hyponatremia).
Palpitations, heart failure, heart attack.
High blood pressure (hypertension).
Vascular inflammation (vasculitis).
Inflammation of the esophagus or pancreas (pancreatitis), narrowing of the large or small intestine (diaphragm-type intestinal stenosis).
Psychotic reactions, hallucinations, confusion, depression, and anxiety.
Asthma, difficulty breathing (dyspnea), bronchospasm.
Yellowing of the eyes and/or skin (jaundice), liver dysfunction, liver damage—especially with prolonged treatment—liver failure, acute liver inflammation (acute hepatitis).
Severe skin reactions such as red, blistering rash (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis/Lyell's syndrome), hair loss (alopecia), red or purple discolored skin spots (purpura), or photosensitivity reactions (triggered by sunlight).
Exceptionally, severe skin infections and soft tissue complications may occur during chickenpox.

Frequency not known (cannot be estimated from available data)

Inflammation of the nasal mucosa (rhinitis).
Numbness and tingling sensation (paresthesia) and optic nerve inflammation (optic neuritis).
Sudden loss of kidney function.
Generalized red, scaly rash with bumps under the skin and blisters, mainly in skin folds, trunk, and upper limbs, accompanied by fever at the beginning of treatment (acute generalized exanthematous pustulosis). Stop taking this medicine if you experience these symptoms and seek immediate medical attention. See also section 2.
Chest pain, which may be a sign of a potentially serious allergic reaction called Kounis syndrome.

Medicines like ibuprofen may be associated with a small increased risk of heart attack ("myocardial infarction") or stroke.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Difenadol

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the carton after EXP. The expiry date is the last day of the month indicated.

This medicine does not require any special storage conditions.

Medicines must not be disposed of via wastewater or household waste. Dispose of unused medicines and their containers at the SIGRE Point at your pharmacy. If you have any doubts, ask your pharmacist how to dispose of medicines and containers you no longer need. This will help protect the environment.

6. Contents of the container and additional information

Composition of Difenadol

The active substance is ibuprofen. Each tablet contains 400 mg of ibuprofen.

The other components are:

Tablet core: microcrystalline cellulose, calcium phosphate, sodium croscarmellose, hypromellose, povidone, stearic acid, talc.

Coating: hypromellose, titanium dioxide (E-171), macrogol, talc.

Appearance of the product and contents of the pack

Film-coated tablets, white or almost white, oblong and biconvex, marked with “I400” on one side and smooth on the other, with a diameter of 14.4 mm x 7.2 mm ± 10%.

Each pack contains 12 or 20 film-coated tablets in Aluminized-PVC blisters.

Marketing Authorization Holder and Manufacturer

Laboratorios Normon, S.A.

Ronda de Valdecarrizo, 6

28760 Tres Cantos – Madrid (Spain)

Date of the most recent review of this leaflet: January 2025

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS): http://www.aemps.gob.es/