Affida max

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AFFFIDA MAX (AFFIDAMAX)

Composition:

Active substance: ibuprofen;

One film-coated tablet contains 400 mg of ibuprofen;

Excipients: lactose monohydrate; maize 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 properties: elongated biconvex film-coated tablets, white to almost white in color, with a line on one side. The line is intended only to facilitate breaking for easier swallowing, not for dividing into equal doses.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. 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 drugs 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) was associated with reduced effect of acetylsalicylic acid on thromboxane formation or platelet aggregation. Although uncertainty exists regarding 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. With occasional, non-systematic use of ibuprofen, such a clinically significant effect is considered unlikely.

Pharmacokinetics.

Ibuprofen is rapidly absorbed in the gastrointestinal tract (GI 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 completely excreted by the kidneys either unchanged or as conjugated complexes, with a negligible 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 influenza.

Contraindications.

• Hypersensitivity to ibuprofen or to any of the excipients of the medicinal product.
• History of hypersensitivity reactions (e.g., asthma, rhinitis, angioneurotic edema, or urticaria) following administration of acetylsalicylic acid or other NSAIDs.
• Active peptic ulcer or gastrointestinal bleeding, or history of recurrent episodes (two or more episodes of confirmed peptic ulcer 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.
• Conditions 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:

• Acetylsalicylic acid: concomitant 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 daily) has been prescribed by a physician.

Experimental data indicate that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when administered concomitantly. Although uncertainty exists regarding extrapolation of these findings to clinical settings, 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 administration 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, angiotensin II receptor antagonists) and diuretics: NSAIDs may reduce the effectiveness of these agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use of an ACE inhibitor, beta-blocker, or angiotensin II antagonist with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including potentially reversible acute renal failure. These interactions should be considered in patients receiving such combinations. Therefore, such combinations should be used with caution, particularly in elderly patients. If treatment is necessary, ensure adequate hydration and consider monitoring renal function at the start 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 administration of mifepristone, 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 when zidovudine is used concomitantly with NSAIDs. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen.
• Quinolone antibiotics: animal data indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones concomitantly may have an increased risk of seizures.
• Cholestyramine: concomitant administration of ibuprofen and cholestyramine may reduce gastrointestinal absorption of ibuprofen. 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 during ibuprofen therapy.
• 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 reduction in ibuprofen dose should be considered when used concomitantly with CYP2C9 inhibitors, especially when high doses of ibuprofen are prescribed to patients taking 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 diseases, or with a history of these conditions.

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 dysfunction.

Cardiovascular and cerebrovascular effects.

Patients with a history of arterial hypertension and/or heart failure should begin treatment with caution (medical or pharmacist consultation is required), as cases of fluid retention, arterial 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 per day), 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 per day) is associated with an increased risk of arterial thrombotic complications.

Patients with uncontrolled arterial 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 assessment of the clinical picture. High doses (2400 mg per day) should be avoided.

The clinical picture should also be carefully evaluated before initiating long-term treatment in patients with risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), especially if high doses of ibuprofen (2400 mg per day) 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 may potentially lead to myocardial infarction.

Effect on female fertility.

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

Gastrointestinal (GI) 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 perforation, which may be fatal, have been reported during treatment with all NSAIDs at any time, regardless of prior warning symptoms or gastrointestinal disorders in the patient's history.

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 advised to report 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 (SSRIs), or antiplatelet agents (e.g., acetylsalicylic acid).

If gastrointestinal bleeding or ulceration occurs 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 suggestive of these reactions appear, ibuprofen should be discontinued immediately and alternative therapy considered (if necessary).

Masking symptoms of concurrent infections.

Affida Max may mask symptoms of infection, potentially leading to delayed initiation of appropriate treatment and thus worsening infection outcomes. This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella. During use of Affida Max for treatment of fever and pain associated with infection, monitoring for infection is recommended. If the patient is not hospitalized but symptoms persist or worsen, medical consultation should be sought.

The product contains lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding.

Fertility.

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Epidemiological data suggest 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, prostaglandin synthesis inhibitors have been associated with increased pre- and post-implantation loss and embryonic/fetal mortality. Additionally, increased incidence of various developmental abnormalities, including cardiovascular malformations, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Pregnancy.

Ibuprofen should not be used during the first two trimesters of pregnancy, except when absolutely necessary. If ibuprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the lowest possible dose should be used for the shortest possible duration.

From the 20th week of pregnancy, use of Affida Max may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of arterial duct constriction following treatment in the second trimester, most of which resolved after discontinuation of therapy. Prenatal monitoring for oligohydramnios and arterial duct constriction should be considered after exposure to ibuprofen for several days starting from the 20th gestational week. Treatment with Affida Max should be discontinued if oligohydramnios or arterial duct constriction is detected.

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

• to the fetus: cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension); renal dysfunction (see above);
• to the mother and neonate (toward the end of pregnancy): possible prolongation of bleeding time, antiplatelet effect, which may occur 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.

Ibuprofen is not recommended during labor.

Onset of labor may be delayed, and its duration may be prolonged, along with increased risk of bleeding in both mother and child.

Breastfeeding period.

In limited studies, ibuprofen has been detected in breast milk at very low concentrations; therefore, it is unlikely to adversely affect a breastfed infant.

Ability to influence 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 heightened attention and rapid reactions.

Dosage and Administration

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

Adults and children aged 12 years and older with body weight >40 kg: 1 tablet per dose. Regular administration at fixed time intervals helps avoid fluctuations in pain intensity. Repeat dose may be taken as needed every 4–6 hours.

Do not exceed the dose of 1200 mg (3 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 lead to intoxication symptoms. 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. Other possible symptoms include tinnitus, headache, and gastrointestinal bleeding. In more severe poisoning, toxic effects on the central nervous system may occur, such as drowsiness, occasionally excitement, disorientation, or coma. Seizures may also develop. In severe intoxication, metabolic acidosis and prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors) may occur. Acute renal failure and liver damage have been reported. In patients with bronchial asthma, asthma exacerbation may occur.

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

Adverse Reactions

The most commonly reported adverse reactions are gastrointestinal (GI) disorders. There is a risk of developing peptic ulcers, perforation, or GI bleeding, sometimes fatal, particularly in elderly patients (see section "Special Warnings and Precautions for Use"). After 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 Warnings and Precautions for Use").

Less frequently, gastritis has been reported.

• Hypersensitivity

Hypersensitivity reactions have been observed during treatment with NSAIDs. These include non-specific allergic reactions and anaphylactic phenomena, respiratory tract reactivity including bronchial asthma, exacerbation of bronchial asthma, bronchospasm or dyspnea, or mixed skin reactions, including various types of rashes, pruritus, urticaria, purpura, angioedema, 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 attention.

• 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 Warnings and Precautions for Use").

• Cardiovascular system disorders

Clinical trial data indicate that the use of ibuprofen, especially at high doses (2400 mg per day), may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

The adverse reactions listed below may be associated with ibuprofen and are classified by frequency and organ systems according to MedDRA. The following frequency groups are used: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data).

The stated frequencies refer to short-term use of the drug 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 and hemolytic anemia
Initial symptoms may include: fever, sore throat, oral mucosal ulcers, 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, angioedema, 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 disturbances
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 hemorrhage
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: hepatic injury
Very rare: liver failure

Skin and subcutaneous tissue disorders

Uncommon: rash, urticaria, pruritus, purpura, photosensitivity reactions
Very rare: severe 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)

Renal and urinary disorders

Very rare: tubulointerstitial nephritis, nephrotic syndrome, renal failure
Acute renal failure, papillary necrosis (especially 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 Warnings and Precautions for Use"), arterial hypertension

Cardiac disorders

Frequency not known: Kounis syndrome

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any 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 any special storage temperature conditions.

Keep out of the reach and sight of children.

Packaging.

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

Prescription status.

Over-the-counter (without prescription).

Manufacturer.

ALKALOID AD Skopje /
ALKALOID AD Skopje.

Manufacturer's address and place of business.

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