Affida

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFFIDA (AFFIDA)

Composition:

Active substance: ibuprofen (ibuprofen);

One film-coated tablet contains 200 mg of ibuprofen;

Excipients: lactose monohydrate; corn starch; sodium croscarmellose; colloidal anhydrous silicon dioxide; microcrystalline cellulose; glycerol dibehenate; Opadry White Y-1-7000 [hypromellose, titanium dioxide (E 171), polyethylene glycol 400].

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: elongated, biconvex film-coated tablets, white to almost white in colour.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. ATC code M01AE01.

Pharmacological Properties

Pharmacodynamics

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID), a propionic acid derivative, which has demonstrated efficacy through inhibition of prostaglandin synthesis. In humans, ibuprofen reduces pain associated with inflammation, swelling, and fever. In addition, ibuprofen reversibly inhibits platelet aggregation.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when these agents are used concomitantly. Some pharmacodynamic studies have shown that administration of single 400 mg doses of ibuprofen within 8 hours before or within 30 minutes after immediate-release acetylsalicylic acid (81 mg) resulted in reduced effect of acetylsalicylic acid on thromboxane formation or platelet aggregation. Although uncertainty exists regarding extrapolation of these data to the clinical setting, the possibility cannot be excluded that regular long-term use of ibuprofen may diminish the cardioprotective effect of low-dose acetylsalicylic acid. With occasional, non-routine use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics

Ibuprofen is rapidly absorbed in the gastrointestinal tract and binds to plasma proteins. Maximum plasma concentration is reached within 1–2 hours after administration.

Ibuprofen is metabolized in the liver into two main metabolites, which are almost entirely excreted by the kidneys either unchanged or as conjugated complexes, along with a small amount of unchanged ibuprofen. Elimination of the drug via the kidneys is complete and rapid. The elimination half-life is approximately 2 hours. No significant differences in pharmacokinetic profile have been observed in elderly patients.

Clinical characteristics

Indications

The medicinal product is indicated for the relief of migraine pain, back pain, dental pain, neuralgia, menstrual pain, and rheumatic and muscular pain.

The medicinal product reduces pain of various origins (headache and other types of pain), decreases inflammation and fever, and alleviates symptoms of cold and flu.

Contraindications

Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.

History of hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, or urticaria) following the administration of acetylsalicylic acid or other NSAIDs.

Active or history of peptic ulcer or duodenal ulcer/bleeding (two or more distinct episodes of confirmed ulceration or bleeding).

History of gastrointestinal bleeding or perforation related to previous NSAID therapy.

Severe heart failure (NYHA class IV), severe renal impairment, or severe hepatic impairment.

Condition associated with an increased risk of bleeding or active bleeding.

Third trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction

• Ibuprofen, like other NSAIDs, should not be used in combination with the following medicinal products:

Acetylsalicylic acid: Concurrent use of ibuprofen with acetylsalicylic acid is generally not recommended due to the potential for increased adverse reactions, except when low-dose acetylsalicylic acid (not exceeding 75 mg per day) has been prescribed by a physician.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation. Although uncertainty exists regarding the extrapolation of these data to the clinical setting, it cannot be excluded that regular long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid. Such a clinically significant effect is considered unlikely with occasional, non-systematic use of ibuprofen.

Other NSAIDs, including selective cyclooxygenase-2 inhibitors: Concomitant use of two or more NSAIDs should be avoided, as this may increase the risk of adverse reactions.

• Ibuprofen should be used with caution in combination with the following medicinal products:

Corticosteroids: Increased risk of gastrointestinal ulcers or bleeding.

Antihypertensive agents (ACE inhibitors, beta-blockers, and angiotensin II receptor antagonists) and diuretics: NSAIDs may reduce the antihypertensive effect of these agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor, beta-blocker, or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration in renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients receiving such combined therapy. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, adequate hydration should be ensured, and monitoring of renal function should be considered at the initiation of combination therapy and periodically thereafter. Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Anticoagulants: NSAIDs may enhance the effect of anticoagulants such as warfarin.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

Cardiac glycosides: NSAIDs may exacerbate cardiac dysfunction, reduce glomerular filtration rate, and increase plasma levels of glycosides.

Lithium: Evidence suggests a potential increase in plasma lithium levels.

Methotrexate: Evidence suggests a potential increase in plasma methotrexate levels.

Phenytoin: Evidence suggests a potential increase in plasma phenytoin levels.

Cyclosporine: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

Zidovudine: Increased risk of hematological toxicity with concomitant use of zidovudine and NSAIDs. Evidence indicates an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are receiving concomitant treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. An increased risk of seizures may occur in patients receiving NSAIDs and quinolone antibiotics concomitantly.

Cholestyramine: Concomitant administration of ibuprofen and cholestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract (GIT); however, the clinical significance of this interaction is unknown.

Sulfonylureas: NSAIDs may potentiate the effects of sulfonylurea agents. Rare cases of hypoglycemia have been reported in patients taking sulfonylureas while using ibuprofen.

Aminoglycosides: NSAIDs may reduce the elimination of aminoglycosides.

CYP2C9 inhibitors: Concomitant use of ibuprofen with CYP2C9 inhibitors may increase ibuprofen exposure (ibuprofen is a CYP2C9 substrate). A reduced dose of ibuprofen should be considered when co-administered with CYP2C9 inhibitors, particularly when high doses of ibuprofen are prescribed to patients receiving voriconazole or fluconazole.

Special precautions for use

Adverse effects can be minimized by using the lowest effective dose required to relieve symptoms for the shortest duration necessary.

In elderly individuals, there is an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforations, which can be fatal.

Respiratory effects

Bronchospasm may occur in patients suffering from bronchial asthma or allergic conditions, or with a history of these diseases.

Other NSAIDs

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.

Systemic lupus erythematosus and mixed connective tissue disease

Ibuprofen should be used with caution in patients with systemic lupus erythematosus or mixed connective tissue disease due to an increased risk of aseptic meningitis.

Renal effects

Caution should be exercised in patients with renal impairment due to the possibility of worsening renal function. There is a risk of renal failure in dehydrated children and adolescents.

Hepatic effects

Caution should be exercised in patients with hepatic impairment.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or heart failure should begin treatment with caution (medical or pharmacist consultation is required), as cases of fluid retention, hypertension, and edema associated with NSAID therapy have been reported.

Clinical trial data indicate that the use of ibuprofen, especially at high doses (up to 2400 mg daily), may be associated with a slightly increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Overall, epidemiological data do not suggest that low-dose ibuprofen (e.g., ≤ 1200 mg daily) is associated with an increased risk of arterial thrombotic complications.

Patients with uncontrolled hypertension, congestive heart failure (NYHA class II–III), diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with ibuprofen only after careful clinical assessment. High doses (2400 mg daily) should be avoided.

Clinical evaluation should also be carefully performed before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., hypertension, hyperlipidemia, diabetes, smoking), especially if high doses of ibuprofen (2400 mg daily) are required.

Cases of Kounis syndrome have been reported in patients receiving ibuprofen therapy. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, which potentially may lead to myocardial infarction.

Effect on female fertility

Limited data suggest that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may impair fertility in women by affecting ovulation. This effect is reversible upon discontinuation of treatment.

Gastrointestinal effects

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated.

Cases of gastrointestinal bleeding, ulcers, or perforations, which may be fatal, have been reported during treatment with all NSAIDs at any stage, regardless of the presence of prior gastrointestinal symptoms or history of gastrointestinal disorders.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients. Such patients should initiate treatment with the lowest available dose.

Patients with a history of gastrointestinal toxicity, particularly elderly patients, should be informed about any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.

Caution should be exercised when treating patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents (e.g., acetylsalicylic acid).

In case of gastrointestinal bleeding or ulceration in patients receiving ibuprofen, treatment should be discontinued immediately.

Serious skin adverse reactions (SSARs)

Serious skin adverse reactions (SSARs), including exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal, have been reported during ibuprofen use (see section "Adverse reactions"). Most such reactions occurred within the first month.

If signs or symptoms suggesting these reactions appear, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Masking symptoms of underlying infections

Ibuprofen may mask symptoms of infectious diseases, potentially delaying the initiation of appropriate treatment and thereby complicating the course of the illness. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. When ibuprofen is used for fever or pain relief in infections, monitoring for infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

The product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding

Fertility

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage, congenital heart defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of therapy.

In animal studies, administration of prostaglandin synthesis inhibitors resulted in increased pre- and post-implantation loss and embryonic/fetal mortality. In addition, increased incidences of various developmental abnormalities, including cardiovascular malformations, have been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Pregnancy

Starting from the 20th week of pregnancy, the use of ibuprofen may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of therapy. Additionally, there are reports of arterial duct constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, ibuprofen should not be used during the first two trimesters of pregnancy except when absolutely necessary. If ibuprofen is used by women attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose for the shortest duration should be used. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. Ibuprofen use should be discontinued if oligohydramnio or arterial duct constriction is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose the following risks:

for the fetus: cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension); renal dysfunction (see above);

for the mother and neonate (at the end of pregnancy): prolonged bleeding time, antiplatelet effect which may develop even at very low doses; inhibition of uterine contractions leading to delayed or prolonged labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy.

Labour and delivery

Ibuprofen is not recommended during labour and delivery.

Onset of labour may be delayed, its duration prolonged, and the risk of bleeding in both mother and child increased.

Lactation period

In limited studies, ibuprofen has been detected in breast milk at very low concentrations, making it unlikely to have a negative effect on the breastfed infant.

Ability to affect reaction speed when driving or operating machinery

The use of NSAIDs may affect reaction speed. If dizziness, drowsiness, fatigue, or visual disturbances occur, patients should refrain from activities requiring high concentration and rapid reactions.

Dosage and Administration

For oral use only. For short-term use only. Patients with gastric disorders are recommended to take tablets with food.

Adults and children aged 12 years and older with body weight >40 kg: 1–2 tablets per dose. To avoid fluctuations in pain intensity, administer at regular intervals. Repeat the dose as needed every 4–6 hours.

Do not exceed 1200 mg (6 tablets) per day.

If symptoms persist for more than 3 days after initiation of treatment or worsen, consult a physician.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Instructions").

Children

Do not use in children under 12 years of age or with body weight <40 kg.

Overdose

Administration of doses exceeding 400 mg/kg in children may cause symptoms of intoxication. In adults, the effect of overdose is less pronounced. The elimination half-life in overdose is 1.5–3 hours.

Symptoms. In most patients, ingestion of clinically significant amounts of NSAIDs causes symptoms such as nausea, vomiting, epigastric pain, and less frequently, diarrhea. Tinnitus, headache, and gastrointestinal bleeding may also occur. In more severe poisoning, toxic effects on the central nervous system may develop, including drowsiness, occasionally excitement, disorientation, or coma. Seizures may sometimes occur. In severe intoxication, metabolic acidosis and prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors) may develop. Acute renal failure and liver damage have been reported. In patients with bronchial asthma, an exacerbation of asthma may occur.

Treatment. Treatment should be symptomatic and supportive, including maintenance of airway patency and monitoring of cardiac function and vital signs until recovery. Oral activated charcoal is recommended if administered within 1 hour after ingestion of a potentially toxic dose. For frequent or prolonged seizures, intravenous diazepam or lorazepam is indicated. Bronchodilators should be used in case of bronchial asthma.

Side effects

The most commonly reported adverse reactions are gastrointestinal disorders. There is a risk of developing peptic ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes fatal, particularly in elderly patients (see section "Special precautions"). Following administration of the drug, cases of nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, and exacerbation of colitis and Crohn’s disease have been reported (see section "Special precautions").

Less frequently, gastritis has been reported.

Hypersensitivity

Hypersensitivity reactions have been observed during treatment with NSAIDs. These include non-specific allergic reactions and anaphylactic reactions, respiratory tract reactivity including bronchial asthma, exacerbation of bronchial asthma, bronchospasm or dyspnea, or mixed skin reactions including various types of rash, pruritus, urticaria, purpura, angioneurotic edema, and very rarely, erythema multiforme and bullous dermatoses (including Stevens–Johnson syndrome and toxic epidermal necrolysis).

Infections and infestations

Cases of skin inflammation exacerbation due to infection (e.g., development of necrotizing fasciitis) have been described during NSAID use. If signs of infection appear or worsen during ibuprofen treatment, the patient should seek immediate medical advice.

Skin and subcutaneous tissue disorders

In exceptional cases, severe skin infections and soft tissue complications may occur during varicella (chickenpox) (see also "Infections and infestations" and section "Special precautions").

Cardiovascular disorders

Clinical trial data indicate that the use of ibuprofen, particularly at high doses (2400 mg per day), may slightly increase the risk of arterial thrombotic events such as myocardial infarction or stroke (see section "Special precautions").

The adverse reactions listed below may be associated with ibuprofen and are classified by frequency and organ system according to MedDRA. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (frequency cannot be estimated from available data).

The stated frequencies apply to short-term use of the medicinal product at a daily dose not exceeding 1200 mg of ibuprofen in oral dosage forms.

Infections and infestations

Uncommon: rhinitis.
Very rare: aseptic meningitis.

Blood and lymphatic system disorders

Very rare: leukopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.
Initial symptoms may include: fever, sore throat, oral mucosal ulceration, flu-like symptoms, severe fatigue, bleeding, and unexplained bruising.

Immune system disorders

Uncommon: hypersensitivity.
Very rare: severe hypersensitivity reactions.
Symptoms may include: facial, tongue, and laryngeal swelling, dyspnea, tachycardia, hypotension (anaphylaxis, angioneurotic edema, or severe shock).

Psychiatric disorders

Uncommon: insomnia, restlessness.
Rare: depression, confusion, hallucinations.

Nervous system disorders

Common: dizziness.
Uncommon: headache, paresthesia, somnolence.
Rare: optic neuritis.

Eye disorders

Uncommon: visual disturbances.
Rare: toxic optic neuropathy.
Frequency not known: photosensitivity reactions.

Ear and labyrinth disorders

Uncommon: hearing impairment.
Rare: tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchial asthma, bronchospasm, dyspnea.

Gastrointestinal disorders

Common: dyspepsia, diarrhea, nausea, vomiting, abdominal pain, flatulence, constipation, melena, hematemesis, gastrointestinal bleeding.
Uncommon: gastritis, duodenal ulcer, gastric ulcer, ulcerative stomatitis, gastrointestinal perforation.
Very rare: pancreatitis.
Frequency not known: colitis and Crohn’s disease.

Hepatobiliary disorders

Uncommon: hepatitis, jaundice, abnormal liver function tests.
Rare: liver injury.
Very rare: liver failure.

Skin and subcutaneous tissue disorders

Uncommon: rash, urticaria, pruritus, purpura.
Very rare: serious skin adverse reactions (SSARs) (including erythema multiforme, exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis).
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), photosensitivity reactions.

Renal and urinary disorders

Very rare: tubulointerstitial nephritis, nephrotic syndrome, renal failure.
Acute renal failure, papillary necrosis (particularly with prolonged use), associated with increased plasma urea levels.

General disorders and administration site conditions

Common: fatigue.
Rare: edema.

Cardiovascular disorders

Very rare: heart failure, myocardial infarction (see section "Special precautions"), arterial hypertension.
Frequency not known: Kounis syndrome.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions

This medicinal product does not require special storage temperature conditions.
Keep out of reach of children.

Packaging

10 tablets in a blister; 1 blister per cardboard box.

Prescription status

Over-the-counter (without prescription).

Manufacturer

ALKALOID AD Skopje.

Manufacturer's address and location of operations

Boulevard Aleksandar Makedonski 12, Skopje, 1000, North Macedonia.